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Effects of exercise stress on the endocannabinoid system in humans under field conditions
Abstract
The effects of physical exercise stress on the endocannabinoid system in humans are almost unexplored. In this prospective study, we investigated in a crossover design and under field conditions at different altitudes the effects of physical exercise on the endocannabinoid system (ECS) in 12 trained healthy volunteers. For determination of alterations on the ECS three different protocols were analyzed: Protocol A (physical exercise at lower altitude) involved strenuous hiking below 2,100 m, whereas Protocol B (physical exercise by active ascent to high altitude) involved hiking up to 3,196 m, an accommodation at the cottage and a descent the next day. Protocol C (passive ascent) included a helicopter ascent to 3,196 m, an overnight stay at this altitude and a flight back to the base camp the following day. The cumulative hiked altitude in Protocol A and B was comparable (~1,650 m). The blood EC concentrations of anandamide increased significantly in Protocol A/B from baseline (T0) 0.12 ± 0.01/0.16 ± 0.02 (mean ± SEM) to 0.27 ± 0.02/0.42 ± 0.02 after exercise (T1) (p < 0.05). Anandamide levels in Protocol C remained stable at 0.20 ± 0.02. We conclude that the ECS is activated upon strenuous exercise whereas the combination with hypoxic stress further increases its activity. The reduced partial pressure of oxygen at high altitude alone did not affect this system. In summary, physical exercise activates the endocannabinoid system, whereas the combination with high altitude enhances this activation. This discloses new perspectives to adaptation mechanisms to physical exercise.
... Their analysis revealed increased plasma AEA content following 45 minutes of moderate-intensity exercise on a treadmill or cycle ergometer. Subsequent human investigations have corroborated heightened blood concentrations of AEA, though intriguingly not of 2-AG, after aerobic exercise durations of 30 to 45 minutes and up to 5 hours [15,[52][53][54]. ...
... The resulting euphoric state, often dubbed the "runner's high," accounts for humans' and other animals' inherent inclination towards voluntary exercise. Notably, exerciseinduced eCB activity in humans seems to be subject to modulation by exercise intensity [15,52,53], aligning with the understanding that the neurobiological repercussions of exercise are intricately linked with its intensity. ...
... Clinically, the stress response can be assessed by evaluating either or both of its components. In response to acute stress, the HPA axis is activated to safeguard the organism's survival [17,52]. Cortisol levels are typically examined to gauge HPA axis activity, with acute stress correlating with elevated levels. ...
Aerobic exercise is a widely adopted practice, not solely for enhancing fitness and reducing the risk of
various diseases but also for its ability to uplift mood and aid in addressing depression and anxiety disorders.
Within the scope of this narrative review, we seek to consolidate current insights into the endocannabinoidmediated regulation of stress and the brain's reward mechanism resulting from engaging in aerobic exercise.
A comprehensive search was conducted across Medline, SPORTDiscus, Pubmed, and Scopus, encompassing
data available until November 30, 2023. This review indicates that a bout of aerobic exercise, particularly of
moderate intensity, markedly augments circulating levels of endocannabinoids - N-arachidonoylethanolamine (AEA) and 2-acylglycerol (2-AG), that significantly contributes to mood elevation and
reducing stress in healthy individuals.
The current understanding of how aerobic exercise impacts mental health and mood improvement is still
unclear. Moderate and high-intensity aerobic exercise modulates stress through a negative feedback
mechanism targeting both the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic nervous
system, thereby facilitating stress regulation crucial role in endocannabinoid synthesis, ultimately
culminating in the orchestration of negative feedback across multiple tiers of the HPA axis, coupled with its
influence over cortical and subcortical brain structures. The endocannabinoid has been observed to govern
the release of neurotransmitters from diverse neuronal populations, implying a universal mechanism that
fine-tunes neuronal activity and consequently modulates both emotional and stress-related responses.
Endocannabinoids further assume a pivotal function within brain reward mechanisms, primarily mediated by
CB1 receptors distributed across diverse cerebral centers. Notably, these endocannabinoids partake in
natural reward processes, as exemplified in aerobic exercise, by synergizing with the dopaminergic reward
system. The genesis of this reward pathway can be traced to the ventral tegmental area, with dopamine
neurons predominantly projecting to the nucleus accumbens, thereby inciting dopamine release in response
to rewarding stimuli.
... Currently, 12 human investigations indicate that exercise increases blood concentrations of eCBs. These studies demonstrated amplification of AEA in plasma after exercise (85)(86)(87)(88)(89)(90), and in most cases, 2-AG remained unchanged (85,86,(88)(89)(90)(91). These studies also showed that 2 congeners of AEA (OEA and PEA) experienced changes like AEA (85,88,91). ...
... Currently, 12 human investigations indicate that exercise increases blood concentrations of eCBs. These studies demonstrated amplification of AEA in plasma after exercise (85)(86)(87)(88)(89)(90), and in most cases, 2-AG remained unchanged (85,86,(88)(89)(90)(91). These studies also showed that 2 congeners of AEA (OEA and PEA) experienced changes like AEA (85,88,91). ...
... During exercise intensity, AEA changes are likely dependent on physiological response but indirectly supported, thus lacking in the full implications. For example, AEA plasma concentrations were elevated after 30-45 min of moderate physical activity involving running and cycling; however, this was not observed with low-or high-vigor exercise based on peak heart rate of 44% and 92%, respectively (86,(88)(89)(90). Human subjects were assigned to periods of moderate, long-duration exercise of hiking in a normoxic environment (4-4.5 h) or in a hypoxic environment (3.5-5.5 h), and the subjects showed a 2-and 3-fold increase in blood AEA, respectively; however, no change in 2-AG was observed (89). ...
The brain and peripheral nervous system provide oversight to muscle physiology and metabolism. Muscle is the largest organ in the body and critical for glucose sensitivity, prevention of diabetes, and control of obesity. The central nervous system produces endocannabinoids (eCBs) that play a role in brain neurobiology, such as inflammation and pain. Interestingly, studies in humans and rodents show that a moderate duration of exercise increases eCBs in the brain and blood and influences cannabinoid receptors. Cannabinoid actions in the nervous system have advanced our understanding of pain, well-being, and disease. Nutrition is an important aspect of brain and eCB physiology because eCBs are biosynthesized from PUFAs. The primary eCB metabolites are derived from arachidonic acid, a 20:4n–6 (ω-6) PUFA, and the n–3 (ω-3) PUFAs, EPA and DHA. The eCBs bind to cannabinoid receptors CB1 and CB2 to exert a wide range of activities, such as stimulating appetite, influencing energy metabolism, supporting the immune system, and facilitating neuroplasticity. A diet containing different essential n–6 and n–3 PUFAs will dominate the formation of specific eCBs, and subsequently their actions as ligands for CB1 and CB2. The eCBs also function as substrates for cyclooxygenase enzymes, including potential substrates for the oxylipins (OxLs), which can be proinflammatory. Together, the eCBs and OxLs act as modulators of neuroinflammation. Thus, dietary PUFAs have implications for exercise responses via synthesis of eCBs and their effects on neuroinflammation. Neurotrophins also participate in interactions between diet and the eCBs, specifically brain-derived neurotrophic factor (BDNF). BDNF supports neuroplasticity in cooperation with the endocannabinoid system (ECS). This review will describe the role of PUFAs in eCB biosynthesis, discuss the ECS and OxLs in neuroinflammation, highlight the evidence for exercise effects on eCBs, and describe eCB and BDNF actions on neuroplasticity.
... A stress is generally defined as any stimulus that threatens the homeostasis of an organism, physiologically or subjectively [1,2]. Similar to a stress, physical exercise activates the ECS and stress-related endocrine pathways such as the HPA axis and catecholaminergic system, important for mood control and alertness [3,4] (Figure 1). ...
... A growing body of studies established that the ECS has a major role in the modulation of the HPA axis [3] i.e., the core stress efferent axis [34,35], and of the catecholaminergic system during stress [4]. When a physiological response is induced under stressful conditions, the ECS has been suggested to mediate or participate in the regulation of its psychological/emotional consequences, impacting on motivation and mood [36]. ...
... The pioneering study of Sparling et al. (2003) reported an increase of AEA and 2-AG after 45 min of cycling or running [45]. Feuerecker and colleagues (2012) interpreted this finding in the way that the intensity of an acute physical activity would be responsible for AEA up-regulation [4]. Altitude would further enhance the effect of an intense exercise session on circulating AEA levels. ...
Evidence suggesting the triangulation of the endocannabinoid system, exercise, and neurological health is emerging. In addition to the endocannabinoids N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonoylglycerol (2-AG), the expanded endocannabinoid system, known as the endocannabinoidome (eCBome), appears to be an important player in this relationship. The eCBome includes several endocannabinoid-like mediators such as N-acylethanolamines and 2-monoacylglycerols, the enzymes involved in their biosynthesis and degradation, and the receptors they affect. This review aims to relate the functional interactions between aerobic exercise, and the molecular and cellular pathways related to endocannabinoids, in the hypothalamus, hippocampus, and the periphery, with special attention given to associations with emotional state, cognition, and mental health. Given the well-documented roles of many eCBome members in regulating stress and neurological processes, we posit that the eCBome is an important effector of exercise-induced central and peripheral adaptive mechanisms that benefit mental health. Gut microbiota imbalance, affecting the gut-brain axis and metabolism, also influences certain eCBome-modulated inflammation pathways. The integrity of the gut microbiota could thus be crucial in the onset of neuroinflammation and mental conditions. Further studies on how the modulation by exercise of the peripheral eCBome affects brain functions could reveal to be key elements in the prevention and treatment of neuropsychological disorders.
... 4,10,11 EVs contain many components of their cells of origin, including RNA, as well as DNA, lipids, and cytosolic and cell-surface proteins. Mechanistic studies indicate that distinct biological signals may be transported by EVs from their cells of origin to specific target cells indicating an important role for EVs in intercellular communication. 4 Given their physicochemical properties, EVs represent ideal transport vehicles for hydrophobic signaling molecules like endocannabinoids 12 and this effect may also be evident under viral infections such as COVID- 19. ...
... A possible explanation for this finding is that ARDS patients were deeply sedated (by benzodiazepines or propofol) and received opioids during mechanical ventilation, whereas respiratory distress in COVID-19 pneumonia patients was much higher as these individuals were awake and needed to breathe spontaneously while receiving only supplemental oxygen without sedation. AEA concentrations are known to increase in the presence of acute 19,20 or chronic 15 stress. This assumption is substantiated by the fact that the levels of the stress hormone cortisol in plasma of these patients were also higher than measured in the more critically ill but sedated ARDS patients. ...
Introduction: Endocannabinoids in COVID-19 have immunomodulatory and anti-inflammatory properties but the functional role and the regulation of endocannabinoid signaling in this pandemic disorder is controversial. To exercise their biologic function, endocannabinoids need to travel across the intercellular space and within the blood stream to reach their target cells. How the lipophilic endocannabinoids are transported in the vascular system and how these hydrophobic compounds cross cell membranes is still unclear. Extracellular vesicles (EVs) are released and incorporated by many cell types including immune cells. EVs are small lipid-membrane covered particles and contain RNA, lipids and proteins. They play an important role in intercellular communication by transporting these signaling molecules from their cells of origin to specific target cells. EVs may represent ideal transport vehicles for lipophilic signaling molecules like endocannabinoids and this effect could also be evident in COVID-19. Materials and Methods: We measured the endocannabinoids anandamide, 2-AG, SEA, PEA and OEA in patients with COVID-19 in EVs and plasma. RNA sequencing of microRNAs (miRNAs) derived from EVs (EV-miRNAs) and mRNA transcripts from blood cells was used for the construction of signaling networks reflecting endocannabinoid and miRNA communication by EVs to target immune cells. Results: With the exception of anandamide, endocannabinoid concentrations were significantly enriched in EVs in comparison to plasma and increased with disease severity. No enrichment in EVs was seen for the more hydrophilic steroid hormones cortisol and testosterone. High EV-endocannabinoid concentrations were associated with downregulation of CNR2 (CB2) by upregulated EV-miRNA miR-146a-5p and upregulation of MGLL by downregulated EV-miR-199a-5p and EV-miR-370-5p suggesting counterregulatory effects. In contrast, low EV-levels of anandamide were associated with upregulation of CNR1 by downregulation of EV-miR-30c-5p and miR-26a-5p along with inhibition of FAAH. Immunologically active molecules in immune cells regulated by endocannabinoid signaling included VEGFA, GNAI2, IGF1, BDNF, IGF1R and CREB1 and CCND1 among others. Discussion and Conclusions: EVs carry immunologically functional endocannabinoids in COVID-19 along with miRNAs which may regulate the expression of mRNA transcripts involved in the regulation of endocannabinoid signaling and metabolism. This mechanism could fine-tune and adapt endocannabinoid effects in recipient cells in relationship to the present biological context.
... Plasma endocannabinoids are upregulated by endurance exercise (5), and in particular by moderate-intensity aerobic exercise (6). Furthermore, plasma AEA levels following endurance exercise are increased for a longer duration at high altitude (7). Decreased oxygen availability, or hypoxia, in addition to endurance exercise seems therefore particularly potent to increase the endocannabinoid tone. ...
... It is thus possible that we missed the long-lasting effects of hypoxia or that the exposure to hypoxia was too short to increase the levels of endocannabinoid ligands. Another parameter to take into consideration is the use of normobaric hypoxia as it was the case in our three studies versus hypobaric hypoxia as used in the aforementioned study (7). Knowing that the physiological adaptations to each of those two types of hypoxia might differ somewhat, this point deserves more investigation (32). ...
Exercise modulates the circulating levels of the endocannabinoids ligands N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) and possibly the levels of their receptors and downstream signaling in skeletal muscle. The aim of the present study was to investigate the regulation of the endocannabinoid system by several exercise paradigms in human skeletal muscle. A second aim was to compare endocannabinoid regulation in healthy and prediabetic people in response to an acute endurance exercise. Blood and muscle samples were taken before and after resistance and endurance exercise in normoxia and hypoxia to measure plasma endocannabinoid levels as well as muscle protein expression of CB1, CB2 and downstream signaling. We found that: 1) an acute resistance exercise session decreased plasma 2-AG and N-palmitoylethanolamine (PEA) levels in normoxia; 2) 4 weeks resistance training decreased plasma AEA, PEA and N-oleoylethanolamine (OEA) levels in both normoxia and hypoxia; 3) an acute moderate intensity endurance exercise increased plasma OEA levels in the healthy and prediabetic groups in normoxia and hypoxia while plasma 2-AG levels increased in the healthy group and AEA in the prediabetic group only in normoxia. The expression of the cannabinoid receptors was only marginally regulated by acute exercise, hypoxia and prediabetes and downstream signaling did not follow the changes detected in the endocannabinoid ligands. Altogether, our results suggest that resistance and endurance exercise regulate the levels of the endocannabinoid ligands and CB1 expression in opposite ways. The physiological impact of the changes observed in the endocannabinoid ligands in human skeletal muscle after exercise needs further investigation.
... It is also possible that THC indirectly increased endocannabinoid levels through enhanced catecholaminergic and glucocorticoid signaling, which are known to cause significant increases in plasma endocannabinoid concentrations. [54][55][56][57][58] THC may also have simply displaced the endogenous ligands, which have a similar protein binding profile, particularly ligands of the GPR55 receptor, which include AEA, OEA, and ARA-S. [59][60][61] Preinhalation levels of AEA and DEA decreased in a stepwise manner between the first and final experimental visit. ...
... Stress can induce glucocorticoid and catecholamine responses that can increase AEA release. 54,55 Future studies may wish to explore if the gradual decrease of baseline AEA represents a conditioned response to the experimental setting. ...
Background: The effects of cannabis are thought to be mediated by interactions between its constituents and the endocannabinoid system. Delta-9-tetrahydrocannabinol (THC) binds to central cannabinoid receptors, while cannabidiol (CBD) may influence endocannabinoid function without directly acting on cannabinoid receptors. We examined the effects of THC coadministered with different doses of CBD on plasma levels of endocannabinoids in healthy volunteers. Methods: In a randomized, double-blind, four-arm crossover study, healthy volunteers (n=46) inhaled cannabis vapor containing 10 mg THC plus either 0, 10, 20, or 30 mg CBD, in four experimental sessions. The median time between sessions was 14 days (IQR=20). Blood samples were taken precannabis inhalation and at 0-, 5-, 15-, and 90-min postinhalation. Plasma concentrations of THC, CBD, anandamide, 2-arachidonoylglycerol (2-AG), and related noncannabinoid lipids were measured using liquid chromatography-mass spectrometry. Results: Administration of cannabis induced acute increases in plasma concentrations of anandamide (+18.0%, 0.042 ng/mL [95%CI: 0.023-0.062]), and the noncannabinoid ethanolamides, docosatetraenylethanolamide (DEA; +35.8%, 0.012 ng/mL [95%CI: 0.008-0.016]), oleoylethanolamide (+16.1%, 0.184 ng/mL [95%CI: 0.076-0.293]), and N-arachidonoyl-L-serine (+25.1%, 0.011 ng/mL [95%CI: 0.004-0.017]) (p<0.05). CBD had no significant effect on the plasma concentration of anandamide, 2-AG or related noncannabinoid lipids at any of three doses used. Over the four sessions, there were progressive decreases in the preinhalation concentrations of anandamide and DEA, from 0.254 ng/mL [95%CI: 0.223-0.286] to 0.194 ng/mL [95%CI: 0.163-0.226], and from 0.039 ng/mL [95%CI: 0.032-0.045] to 0.027 ng/mL [95%CI: 0.020-0.034] (p<0.05), respectively. Discussion: THC induced acute increases in plasma levels of anandamide and noncannabinoid ethanolamides, but there was no evidence that these effects were influenced by the coadministration of CBD. It is possible that such effects may be evident with higher doses of CBD or after chronic administration. The progressive reduction in pretreatment anandamide and DEA levels across sessions may be related to repeated exposure to THC or participants becoming less anxious about the testing procedure and requires further investigation. The study was registered on clinicaltrials.gov (NCT05170217).
... The study conducted by Sparling et al. was arguably the first showing that moderate exercises led to the increased level of AEA but not 2-AG in the sera of healthy subjects after 50 min of treadmill running or cycling on a stationary bike at the level of 70-80% of maximum heart rate [90]. Other studies also indicated that PA, especially at medium intensity, led to the increased blood level of AEA, whereas 2-AG remained unchanged [91][92][93][94]. Heyman et al. revealed the link between significantly increased plasma AEA, OEA, and PEA levels during intense exercise followed by 15 min of recovery and elevated serum brain-derived neurotrophic factor (BDNF) levels, thereby indicating an important role of the ECS in the production of neuroplastic and antidepressant effects triggered by PA. ...
... These effects probably arise from the fact that CB1R shares similar localization in the midbrain with dopamine receptors and may enhance the activity of dopaminergic neurons in ventral tegmentum and substantia nigra [106]. Interestingly, observed decreased blood eCBs levels after PA among obese individuals are opposite to those described in the studies involving healthy patients, which, as was mentioned above, indicated increased concentrations of AEA and/or 2-AG [91][92][93][94]98,99]. A similar concern deals with the altered expression of cannabinoid receptors. ...
Rapidly increasing worldwide prevalence of obesity and related pathologies encompassing coronary heart disease, hypertension, metabolic syndrome, or type 2 diabetes constitute serious threats to global health and are associated with a significantly elevated risk of premature death. Considering the enormous burden of these pathologies, novel therapeutic and preventive patterns are indispensable. Dysregulation of one of the most complex biological systems in the human body namely, the endocannabinoid system (ECS) may result in metabolic imbalance and development of insulin resistance, type 2 diabetes, or non-alcoholic fatty liver disease. Furthermore, many studies showed that physical exercises, depending on their type, intensity, and frequency, exert various alterations within the ECS. Emerging evidence suggests that targeting the ECS via physical activity may produce robust beneficial effects on the course of metabolic pathologies. However, the data showing a direct correlation between the ECS and physical activity in the aspect of metabolic health are very scarce. Therefore, the aim of this review was to provide the most up-to-date state of knowledge about the interplay between the ECS activity and physical exercises in the novel therapeutic and preventive approach toward metabolic pathologies. We believe that this paper, at least in part, will fulfill the existing gap in knowledge and encourage researchers to further explore this very complex yet interesting link between the ECS, its action in physical activity, and subsequent positive outcomes for metabolic health.
... Inspection of the effect sizes (Fig. 2a) suggests that moderate-intensity exercise is associated with greater increases in AEA as compared with low-intensity exercise, as revealed by the systematic review. 48 Consistent with observations from the systematic review, in general, prescribed moderate-intensity exercise was associated with greater increases in AEA as compared with preferred (Fig. 2a). In addition to comparing preferred versus prescribed, Brellenthin et al. 40 examined the impact of regular physical activity on exercise-related changes in eCBs across three groups: low ( £ 60 min MVPA per week), moderate (150-299 min MVPA per week), and high ( ‡ 300 MVPA per week) physical activity groups. ...
... Indeed, several studies report that moderateintensity exercise is associated with greater increases in AEA as compared with other intensities (Fig. 3). 31,40,46,48,56,58,59 There is also initial evidence for an inverted U-shaped effect of exercise intensity on AEA concentrations, such that moderate intensity is associated with the greatest increases; however, this notion is based on results of one study that examined high-intensity exercise (i.e., *90% age-adjusted MHR). 31 However, the idea that the optimal eCB response may be at moderate-intensity exercise fits with prior data on other outcomes. ...
Introduction: The endocannabinoid (eCB) system plays a key role in maintaining homeostasis, including the regulation of metabolism and stress responses. Chronic stress may blunt eCB signaling, and disruptions in eCB signaling have been linked to stress-related psychiatric disorders and physical health conditions, including anxiety, depression, post-traumatic stress disorder (PTSD), diabetes, and obesity. Pharmacological and nonpharmacological behavioral interventions (e.g., exercise) that target the eCB system may be promising therapeutic approaches for the prevention and treatment of stress-related diseases. In this study, we perform a systematic review and the first meta-analysis to examine the impact of exercise on circulating eCB concentrations. Materials and Methods: We performed a review of the MEDLINE (PubMed) database for original articles examining the impact of exercise on eCBs in humans and animal models. A total of 262 articles were screened for initial inclusion. Results: Thirty-three articles (reporting on 57 samples) were included in the systematic review and 10 were included in the meta-analysis. The majority of samples that measured anandamide (AEA) showed a significant increase in AEA concentrations following acute exercise (74.4%), whereas effects on 2-arachidonoylglycerol (2-AG) were inconsistent. The meta-analysis, however, revealed a consistent increase in both AEA and 2-AG following acute exercise across modalities (e.g., running, cycling), species (e.g., humans, mice), and in those with and without pre-existing health conditions (e.g., PTSD, depression). There was substantial heterogeneity in the magnitude of the effect across studies, which may relate to exercise intensity, physical fitness, timing of measurement, and/or fasted state. Effects of chronic exercise were inconsistent. Conclusions: Potential interpretations and implications of exercise-induced mobilization of eCBs are discussed, including refilling of energy stores and mediating analgesic and mood elevating effects of exercise. We also offer recommendations for future work and discuss therapeutic implications for exercise in the prevention and treatment of stress-related psychopathology.
... One such mechanism is the endocannabinoid (ECB) system, which consists of cannabinoid receptors found at peripheral, spinal, and supraspinal pain processing sites (63,71) and endogenous ligand agonists, including anandamide and 2-arachidonoylglycerol (2AG). Endocannabinoids are synthesized and rapidly released from cells in response to stressful conditions such as exercise (10). Studies have reported increased concentrations of endocannabinoids following exercise in humans (10,60), suggesting the ECB system might contribute to EIH. ...
... Endocannabinoids are synthesized and rapidly released from cells in response to stressful conditions such as exercise (10). Studies have reported increased concentrations of endocannabinoids following exercise in humans (10,60), suggesting the ECB system might contribute to EIH. This hypothesis is supported by the dense expression of ECB receptors on A-delta and C-delta primary afferents (22), which are activated during muscle contractions to produce alterations in circulating concentrations of endocannabinoids (39). ...
Aim:
This study aimed to investigate and compare the magnitude of exercise-induced hypoalgesia (EIH) with low intensity blood flow restriction (BFR) resistance exercise (RE) at varying pressures to other intensities of resistance exercise and examine endogenous mechanisms of pain reduction.
Methodology:
Twelve individuals performed four experimental trials involving unilateral leg press exercise in a randomised crossover design: low load RE at 30% of one repetition maximum (1RM), high load RE (70% 1RM) and BFR-RE (30% 1RM) at a low and high pressure. BFR pressure was prescribed relative to limb occlusion pressure at 40% and 80% for the low- and high-pressure trials. Pressure pain thresholds (PPT) were assessed before, 5-min and 24-h following exercise in exercising and non-exercising muscles. Venous blood samples were collected at the same timepoints to determine plasma concentrations of beta-endorphin and 2-arachidonoylglycerol.
Results:
High pressure BFR-RE increased PPTs in the exercising limb to a greater extent than all other trials. Comparable systemic EIH effects were observed with HLRE and both BFR-RE trials. PPTs in the exercising limb remained elevated above baseline at 24-h post-exercise following both BFR-RE trials. Post-exercise plasma beta-endorphin concentration was elevated during the BFR-RE trials. No changes to 2-arachidonoylglycerol concentration were observed.
Conclusion:
High pressure BFR-RE causes a greater EIH response in the exercising limb that persists for up to 24-h following exercise. The reduction in pain sensitivity with BFR-RE is partly driven by endogenous opioid production of beta-endorphin. BFR-RE should be introduced as a possible pain-modulation tool in individuals with acute and chronic pain.
... Endocannabinoids have been shown to have antinociceptive effects in models of acute pain in animals and humans [69,70] by binding to CB1 and CB2 receptors found in the PNS and at spinal and supraspinal pain processing sites [68,69]. Endocannabinoids are synthesised from arachidonic acid and can be released from cells immediately after their synthesis [71] in response to stress of a physical nature [49]. Several studies have observed systemic elevations in circulating concentrations of AEA following exercise [52,[71][72][73], suggesting endocannabinoids play a role in EIH. ...
... Endocannabinoids are synthesised from arachidonic acid and can be released from cells immediately after their synthesis [71] in response to stress of a physical nature [49]. Several studies have observed systemic elevations in circulating concentrations of AEA following exercise [52,[71][72][73], suggesting endocannabinoids play a role in EIH. This would be supported by the dense expression of CB receptors on A-delta and C-delta primary afferents [74] which are activated during muscle contractions to produce alterations in circulating concentrations of endocannabinoids [6]. ...
Exercise-induced hypoalgesia is characterised by a reduction in pain sensitivity following exercise. Recently, low intensity exercise performed with blood flow restriction has been shown to induce hypoalgesia. The purpose of this manuscript is to discuss the mechanisms of exercise-induced hypoalgesia and provide rationale as to why low intensity exercise performed with blood flow restriction may induce hypoalgesia. Research into exercise-induced hypoalgesia has identified several potential mechanisms, including opioid and endocannabinoid-mediated pain inhibition, conditioned pain modulation, recruitment of high threshold motor units, exercise-induced metabolite production and an interaction between cardiovascular and pain regulatory systems. We hypothesise that several mechanisms consistent with prolonged high intensity exercise may drive the hypoalgesia effect observed with blood flow restriction exercise. These are likely triggered by the high level of intramuscular stress in the exercising muscle generated by blood flow restriction including hypoxia, accumulation of metabolites, accelerated fatigue onset and ischemic pain. Therefore, blood flow restriction exercise may induce hypoalgesia through similar mechanisms to prolonged higher intensity exercise, but at lower intensities, by changing local tissue physiology, highlighting the importance of the blood flow restriction stimulus. The potential to use blood flow restriction exercise as a pain modulation tool has important implications following acute injury and surgery, and for several load compromised populations with chronic pain.
... Besides the sympathoadrenal and glucocorticoid system, the endocannabinoid system (ECS) plays an important role in coping with such stress reactions. Its lipid mediators the endocannabinoids (ECs) and chemically related N-acylethanolamides (NAEs) are very related with acclimatization processes at several physiological lines (e.g., psychological, metabolic, peripheral, and central nervous system) in response to environmental factors such as hypobaric hypoxia and temperature to reach physiological homeostasis (Campolongo et al., 2009Richard et al., 2009;Chouker et al., 2010;Dlugos et al., 2012;Feuerecker et al., 2012;Hauer et al., 2013Hauer et al., , 2014Morena et al., 2014;Neumeister et al., 2015;Hanlon et al., 2016). ...
... Apparently, the time course and the long-term impact of the physical conditions seem to play an important role in the development of the physiological answer. In addition, Feuerecker et al. (2012) evidenced no changes in the human ECS under short-term hypobaric hypoxia (altitude of 3,196 m) but only in its combination with physical effort. The opposite effect of an enhanced EC response was probably due to the study design that displayed an acute stress model. ...
The Antarctic continent is an environment of extreme conditions. Only few research stations exist that are occupied throughout the year. The German station Neumayer III and the French-Italian Concordia station are such research platforms and human outposts. The seasonal shifts of complete daylight (summer) to complete darkness (winter) as well as massive changes in outside temperatures (down to -80°C at Concordia) during winter result in complete confinement of the crews from the outside world. In addition, the crew at Concordia is subjected to hypobaric hypoxia of ∼650 hPa as the station is situated at high altitude (3,233 m). We studied three expedition crews at Neumayer III (sea level) (n = 16) and two at Concordia (high altitude) (n = 15) to determine the effects of hypobaric hypoxia on hormonal/metabolic stress parameters [endocannabinoids (ECs), catecholamines, and glucocorticoids] and evaluated the psychological stress over a period of 11 months including winter confinement. In the Neumayer III (sea level) crew, EC and n-acylethanolamide (NAE) concentrations increased significantly already at the beginning of the deployment (p < 0.001) whereas catecholamines and cortisol remained unaffected. Over the year, ECs and NAEs stayed elevated and fluctuated before slowly decreasing till the end of the deployment. The classical stress hormones showed small increases in the last third of deployment. By contrast, at Concordia (high altitude), norepinephrine concentrations increased significantly at the beginning (p < 0.001) which was paralleled by low EC levels. Prior to the second half of deployment, norepinephrine declined constantly to end on a low plateau level, whereas then the EC concentrations increased significantly in this second period during the overwintering (p < 0.001). Psychometric data showed no significant changes in the crews at either station. These findings demonstrate that exposition of healthy humans to the physically challenging extreme environment of Antarctica (i) has a distinct modulating effect on stress responses. Additionally, (ii) acute high altitude/hypobaric hypoxia at the beginning seem to trigger catecholamine release that downregulates the EC response. These results (iii) are not associated with psychological stress.
... Concurrently, the ECS facilitates behaviors hampered by stress reaction for instance feeding in addition to sleep patterns. During chronic stress the insufficient escalation of 2-AG / CB1R signaling secondary to variable stressful conditions result in downregulation of CB1R signaling in the medial prefrontal cortex(PFC) along with hypothalamus, initiating a state referred to ''hypo cannabinoid state '' [59]. ...
Aerobic exercise isa broadly used methodology, apart from escalating fitness, decreasing risk of different diseases, it gets further used for mood enhancement, tackling depression and anxiety. Earlier we had detailed role of endocannabinoids(eCBs) in obesity initially when rimonabant, a cannabinoid-1 receptor (CB1R) antagonist was observed to be efficacious in obesity treatment although later discarded, due to endocannabinoids role in raj yoga meditation by the liberation of anandamide. Here we have detailed crosstalk amongst aerobic exercises along with endurance running regarding management of stress as well as brain' s reward system. Additionally, it delves into ECS along with its signalling modes, displays the aftermath of aerobic exercises on HPA axis regarding physiological controlling of stress, updating neural circuits underscoring reward in addition to mood enhancement in the form of results of aerobic exercises performance. The present insight over the manner aerobic exercise influences mental health as well as mood enhancement continues to be uncertain. Moderate along with high intensity aerobic exercise modulate stress via negative feedback which targets hypothalamic-pituitary-adrenal (HPA) axis along with sympathetic nervous system (SNS) therefore promoting stress controlling having a key part in eCBs generation with finally cessation in mediating negative feedback organization over plethora of HPA axis tiers correlated with its impact over cortical along with subcortical brain structures. The eCBs have been observed in controlling liberation of neurotransmitters, from variable neuronal populations, pointing to a ubiquitous mode which finetunes neuronal actions &sequentially modulate emotional & stress correlated reactions. Furthermore, eCBs, possess part in brain rewards working basically modulate by CB1R organized over variable cerebral centres. Noticeably these ECBs participate in natural rewards events, the way exemplified by aerobic exercise in getting synergistic with dopaminergic brain' s reward system. Generation of these reward can be traced back to ventral tegmental are (VTA) with dopamine neurons basically projecting to nucleus accumbens (NAc) therefore stimulating dopamine liberation in reaction to rewarding stimuli.
... AEA increased more at higher altitudes; nevertheless, these environmental conditions alone did not influence the control group (static, taken to the same altitude by helicopter). Similar to the results of other studies regarding the ECS, the 2-Ag levels were not modified [109]. ...
The endocannabinoid system (ECS) is involved in various processes, including brain plasticity, learning and memory, neuronal development, nociception, inflammation, appetite regulation, digestion, metabolism, energy balance, motility, and regulation of stress and emotions. Physical exercise (PE) is considered a valuable non-pharmacological therapy that is an immediately available and cost-effective method with a lot of health benefits, one of them being the activation of the endogenous cannabinoids. Endocannabinoids (eCBs) are generated as a response to high-intensity activities and can act as short-term circuit breakers, generating antinociceptive responses for a short and variable period of time. A runner’s high is an ephemeral feeling some sport practitioners experience during endurance activities, such as running. The release of eCBs during sustained physical exercise appears to be involved in triggering this phenomenon. The last decades have been characterized by an increased interest in this emotional state induced by exercise, as it is believed to alleviate pain, induce mild sedation, increase euphoric levels, and have anxiolytic effects. This review provides information about the current state of knowledge about endocannabinoids and physical effort and also an overview of the studies published in the specialized literature about this subject.
... [13][14][15][16][17] The increase in circulating oxylipins is generally more minor after low-exercise intensity or very short exercise than more intense or prolonged exercise bouts. [13][14][15][16][17] Circulating levels of AEA [18][19][20][21][22][23] and of the eCBs analogues PEA and OEA 24 also increase in response to acute endurance exercise in humans. ...
Background
Fatty acid-derived lipid mediators including oxylipins, endocannabinoids (eCBs), and their analogues, have emerged as key metabolites in the inflammatory and immune response to physiological stressors.
Methods
This report was based on a sub-study and secondary analyses the ACTIBATE single-center unblinded randomized controlled trial (ClinicalTrials.gov ID: NCT02365129). The study was performed in the Sport and Health University Research Institute and the Virgen de las Nieves University Hospital of the University of Granada. Eligible participants were young, sedentary adults with no chronic diseases. Here, we performed both an acute endurance and resistance exercise sub-studies (n = 14 and 17 respectively), and a 24-week supervised exercise intervention, combining endurance and resistance exercise training at moderate-intensity (MOD-EX) or vigorous-intensity (VIG-EX) exercise groups, in young sedentary adults. Randomization was performed by unrestricted randomization. Plasma levels of oxylipins, eCBs, and their analogues were measured using liquid chromatography-tandem mass spectrometry.
Findings
Both endurance and resistance exercise increased by +50% the plasma levels of dihomo-γ-linolenic acid and arachidonic acid (AA) omega-6 derived oxylipins, as well as eicosapentaenoic acid and docosahexaenoic acid omega-3 derived after 3 and 120 min of the bout of exercise (all η2 ≥ 0.219 and P ≤ 0.039). These exercise modalities also increased the levels of anandamide and eCBs analogues (+25%). 145 young sedentary adults were assigned to a control (CON, n = 54), a MOD-EX (n = 48) or a VIG-EX (n = 43). 102 participants were included in the final long-term analyses (CON, n = 36; MOD-EX, n = 33; and VIG-EX, n = 33) of the trial. After 24-week of supervised exercise, MOD-EX decreased plasma levels of omega-6 oxylipins, concretely linoleic acid (LA) and adrenic acid derived oxylipins, and the eCBs analogues OEA and LEA in comparison to the CON (all P ≤ 0.021). VIG-EX decreased LA-derived oxylipins and LEA compared to CON. No relevant adverse events were recorded.
Interpretation
Endurance and resistance exercises acutely increased plasma levels of oxylipins, eCBs, and their analogues, whereas 24 weeks of exercise training decreased fasting plasma levels of omega-6 oxylipins, and eCBs analogues in young, sedentary adults.
... Previous work among heterogeneous populations globally showed www.nature.com/scientificreports/ that NAEs significantly increased upon 30 min of exercise of moderate intensity or over in a short-term manner 13,14,22,47 . Interestingly, NAEs levels were also enhanced with a longer aerobic demand lasting up to 5 h in hypoxic conditions 15 . Some investigators have shown that AEA and OEA increased after 20 min of moderate exercise, while 2-AG, PEA and 2-OG remained stable for adult women reporting major depressive disorder 48 . ...
The extended endocannabinoid system, also termed endocannabinoidome, participates in multiple metabolic functions in health and disease. Physical activity can both have an acute and chronic impact on endocannabinoid mediators, as does diet. In this crossover randomized controlled study, we investigated the influence of diet on the peripheral response to acute maximal aerobic exercise in a sample of active adult women (n = 7) with no underlying metabolic conditions. We compared the impact of 7-day standardized Mediterranean diet (MedDiet) and control diet inspired by Canadian macronutrient intake (CanDiet) on endocannabinoidome and short-chain fatty acid metabolites post maximal aerobic exercise. Overall, plasmatic endocannabinoids, their congeners and some polyunsaturated fatty acids increased significantly post maximal aerobic exercise upon cessation of exercise and recovered their initial values within 1 h after exercise. Most N-acylethanolamines and polyunsaturated fatty acids increased directly after exercise when the participants had consumed the MedDiet, but not when they had consumed the CanDiet. This impact was different for monoacylglycerol endocannabinoid congeners, which in most cases reacted similarly to acute exercise while on the MedDiet or the CanDiet. Fecal microbiota was only minimally affected by the diet in this cohort. This study demonstrates that endocannabinoidome mediators respond to acute maximal aerobic exercise in a way that is dependent on the diet consumed in the week prior to exercise.
... Not only the intensity of physical activity determines the alteration of EC in healthy adults (Feuerecker et al., 2012), but also the duration and subjects characteristics are important as well (Charytoniuk et al., 2020). Some studies showed that chronic exercises might be associated with the upregulation of EC receptor (CB1R) in the hippocampus of mice (Ferreira-Vieira et al., 2014;Brellenthin and Koltyn, 2016). ...
As human life expectancy increases, cognitive decline and memory impairment threaten independence and quality of life. Therefore, finding prevention and treatment strategies for memory impairment is an important health concern. Moreover, a better understanding of the mechanisms involved underlying memory preservation will enable the development of appropriate pharmaceuticals drugs for those who are activity limited. Exercise training as a non-pharmacological tool, has been known to increase the mean lifespan by maintaining general body health and improving the cardiovascular and nervous systems function. Among different exercise training protocols, aerobic exercise has been reported to prevent the progression of memory decline, provided adequate exertion level, duration, and frequency. Mechanisms underlying exercise training effects on memory performance have not been understood yet. Convergent evidence suggest several direct and indirect mechanisms at molecular and supramolecular levels. The supramolecular level includes improvement in blood circulation, synaptic plasticity and neurogenesis which are under controls of complex molecular signaling of neurotransmitters, neurotrophic factors, exerkines, and epigenetics factors. Among these various factors, irisin/BDNF signaling seems to be one of the important mediators of crosstalk between contracted skeletal muscles and the brain during exercise training. This review provides an affordable and effective method to improve cognitive function in old ages, particularly those who are most vulnerable to neurodegenerative disorders.
... Moreover, precision nutrition would also help understand the nature of inter-individual postprandial eCBome and microbiome responses. Additionally, a plethora of evidence [238][239][240][241][242][243][244][245] suggests that physical activity/exercise acts as a strong influencer of both these 'omes,' thereby modifying their baseline signalling tone and determining whether a given diet augments too little or too much the output of one rather than the other given mediator derived from fatty acids or commensal microorganisms. ...
The discovery of the endocannabinoidome (eCBome) is evolving gradually with yet to be elucidated functional lipid mediators and receptors. The diet modulates these bioactive lipids and the gut microbiome, both working in an entwined alliance. Mounting evidence suggests that, in different ways and with a certain specialisation, lipid signalling mediators such as N-acylethanolamines (NAEs), 2-monoacylglycerols (2-MAGs), and N-acyl-amino acids (NAAs), along with endocannabinoids (eCBs), can modulate physiological mechanisms underpinning appetite, food intake, macronutrient metabolism, pain sensation, blood pressure, mood, cognition, and immunity. This knowledge has been primarily utilised in pharmacology and medicine to develop many drugs targeting the fine and specific molecular pathways orchestrating eCB and eCBome activity. Conversely, the contribution of dietary NAEs, 2-MAGs and eCBs to the biological functions of these molecules has been little studied. In this review, we discuss the importance of (Wh) olistic (E)ndocannabinoidome-Microbiome-Axis Modulation through (N) utrition (WHEN), in the management of obesity and related disorders.
... It should be noted that the decrease in pain intensity was significantly higher in G2, followed by G1, when compared to G3, which indicates that the effects of the therapeutic exercise programme associated with aerobic exercise (G2) and the exercise programme therapeutic exercises (G1) alone were more efficient in relieving pain compared with the aerobic exercise programme performed alone (G3). Elimination of pain in G2 group may result from the association of the effects promoted locally by therapeutic exercises with the systemic effects of hypoalgesia resulting from the release of beta-endorphins,35 activation of cannabinoids receptors,36 pain modulation by the cardiovascular system,22 or the activation of the descending pathways during the aerobic exercise.23 ...
Background
Pain and anxiety contribute to decreasing quality of life related to oral health in patients with temporomandibular disorders (TMD). Evidence-based practice has shown that therapeutic and aerobic exercise programs are adequate strategies for modifying these factors.
Objective
Assess the effects of aerobic exercise on pain, anxiety and quality of life related to oral health in patients with TMD.
Methods
Forty-five patients diagnosed with TMD were divided into three groups of 15 participants: a therapeutic exercise program (G1, mean 26.9±5.5 years), a therapeutic and aerobic exercise program (G2, mean 26±4.4 years) and an aerobic exercise program (G3, mean 24.9±3.4 years). Pain intensity was assessed using a numerical rating scale (NRS), anxiety level and quality of life related to oral health through GAD-7 and OHIP-14, respectively. These parameters were evaluated twice at baseline (T0a/T0b), ending 8-week intervention period (T1), and 8-12 weeks after ending intervention (T2).
Results
NRS significantly decreased in G1 (mean difference T0a/T1=5.2, p˂0.001), G2 (mean difference T0a/T1=6.0, p˂0.001) and G3 (mean difference T0a/T1=2.2, p=0.001). OHIP-14 significantly decreased in G1 (mean difference T0a/T1=13.5, p˂0.001) and G2 (mean difference T0a/T1=15.8, p ˂ 0.001) but not in G3 (mean difference T0a/T1=1.2, p=0.55). There were no significant differences between groups regarding GAD-7. Between T1 and T2 there were no significant differences in variables.
Conclusion
Therapeutic exercises and therapeutic excercises combined with aerobic exercise groups had a significant decrease in pain and oral health related quality of life at 8 and 12 weeks. These decreases were not seen for the aerobic exercise group.
... Interestingly, it also modulates the eCB system balance, a fact suggesting its relevance from both a neurobiological and psychosomatic perspective (90). Indeed, increased eCB concentrations were found following a simple jog, bike ride, hike, and other moderate intensity aerobic exercises, while the differences of FAAH hydrolytic activity in active and sedentary individuals result in different AEA plasma levels (91)(92)(93)(94). ...
Studies investigating the psychosomatic effects of social isolation in animals have shown that one of the physiologic system that gets disrupted by this environment-affective change is the Endocannabinoid System. As the levels of endocannabinoids change in limbic areas and prefrontal cortex during stressful times, so is the subject more prone to fearful and negative thoughts and aggressive behavior. The interplay of social isolation on the hypothalamic-pituitary-adrenal axis and cannabinoid tone triggers a vicious cycle which further impairs the natural body's homeostatic neuroendocrine levels and provokes a series of risk factors for developing health complications. In this paper, we explore the psychosomatic impact of prolonged quarantine in healthy individuals, and propose management and coping strategies that may improve endocannabinoid tone, such as integration of probiotics, cannabidiol, meditation, and physical exercise interventions with the aim of supporting interpersonal, individual, and professional adherence with COVID-19 emergency public measures whilst minimizing their psycho-physical impact.
... Intriguingly, the one participant who even reported a subjective runner's high during the walking condition was found to have an increase of plasma eCBs during walking that was roughly comparable to the average increase in the RUN condition. This result is in line with earlier reports finding an increase of eCB levels following hiking (Feuerecker et al., 2012), masturbating , or singing (Stone et al., 2018). ...
A runner's high describes a sense of well-being during endurance exercise characterized by euphoria and anxiolysis. It has been a widespread belief that the release of endogenous opioids, such as endorphins, underlie a runner's high. However, exercise leads to the release of two classes of rewarding molecules, endocannabinoids (eCBs) and opioids. In mice, we have shown that core features of a runner's high depend on cannabinoid receptors but not opioid receptors. In the present study, we aimed to corroborate in humans that endorphins do not play a significant role in the underlying mechanism of a runner's high. Thus, we investigated whether the development of two core features of a runner's high, euphoria and reduced anxiety levels, depend on opioid signaling by using the opioid receptor antagonist naltrexone (NAL) in a double-blind, randomized, placebo (PLA)-controlled experiment. Participants (N=63) exhibited increased euphoria and decreased anxiety after 45 min of running (RUN) on a treadmill in a moderate-intensity range compared to walking (WALK). RUN led to higher plasma levels of the eCBs anandamide (AEA) and 2-arachidonoglycerol (2-AG). Opioid blockade did not prevent the development of euphoria and reduced anxiety as well as elevation of eCB levels following exercise. Moreover, the fraction of participants reporting a subjective runner's high was comparable in the NAL and PLA-treated group. Therefore, this study indicates that the development of a runner's high does not depend on opioid signaling in humans, but makes eCBs strong candidates in humans, as previously shown in mice.
... Although present times are much overwhelmed with a vast amount of research that provides indisputable evidence of the beneficial effects of exercises on neurological pathologies, the exact biological systems and their mechanisms involved in this process are still questionable and widely discussed. Over the last decade, the endocannabinoid system was extensively studied for its correlation with physical activity, which was recognized as a factor that notably modifies this essential biological system and its related molecular pathways [8,9]. Some recent studies demonstrated that plasma levels of endocannabinoids are notably higher after physical activity and might be associated with the long-term beneficial effects on neurophysiology, namely, mood, appetite, mental health, memory, as well as cognitive processes [10][11][12]. ...
The worldwide prevalence of neurological and neurodegenerative disorders, such as depression or Alzheimer’s disease, has spread extensively throughout the last decades, becoming an enormous health issue. Numerous data indicate a distinct correlation between the altered endocannabinoid signaling and different aspects of brain physiology, such as memory or neurogenesis. Moreover, the endocannabinoid system is widely regarded as a crucial factor in the development of neuropathologies. Thus, targeting those disorders via synthetic cannabinoids, as well as phytocannabinoids, becomes a widespread research issue. Over the last decade, the endocannabinoid system has been extensively studied for its correlation with physical activity. Recent data showed that physical activity correlates with elevated endocannabinoid serum concentrations and increased cannabinoid receptor type 1 (CB1R) expression in the brain, which results in positive neurological effects including antidepressant effect, ameliorated memory, neuroplasticity development, and reduced neuroinflammation. However, none of the prior reviews presented a comprehensive correlation between physical activity, the endocannabinoid system, and neuropathologies. Thus, our review provides a current state of knowledge of the endocannabinoid system, its action in physical activity, as well as neuropathologies and a possible correlation between all those fields. We believe that this might contribute to finding a new preventive and therapeutic approach to both neurological and neurodegenerative disorders.
... On the other hand, many studies have shown that the application of therapeutic exercise in this population produces a maintenance of change for the medium term [9,10]. Changes generated by therapeutic exercise are produced by some neuromodulatory mechanisms, such as the analgesia produced by the opioid route or the analgesia produced by releasing endogenous cannabinoids [11][12][13][14][15]. ...
Objective:
To compare the effectiveness of a biobehavioral approach with and without orthopedic manual physical therapy on the intensity and frequency of pain in patients diagnosed with nonspecific chronic low back pain.
Methods:
A single-blind randomized controlled trial. Fifty patients were randomly allocated into two groups: one group received biobehavioral therapy with orthopedic manual physical therapy, and the other group received only biobehavioral therapy. Both groups completed a total of eight sessions, with a frequency of two sessions per week. The somatosensory, physical, and psychological variables were recorded at baseline and during the first and third month after initiation of treatment.
Results:
In both groups, the treatment was effective, presenting significant differences for all the variables in the time factor. There were no significant differences between groups in intensity or frequency of pain, with a large effect size (>0.80), but there were intragroup differences for both intervention groups at one- and three-month follow-up. There were also no significant differences between groups in the secondary variables during the same follow-up period.
Conclusions:
The results of this study suggest that orthopedic manual physical therapy does not increase the effects of a treatment based on biobehavioral therapy in the short or medium term, but these results should be interpreted with caution.
... Other studies have further demonstrated the close relationship between the intensity and type of physical exercise and ECS activity. In particular, while an exercise of moderate intensity was confirmed to increase the plasma levels of AEA in human volunteers, surprisingly no changes in plasma ECs were observed following a very-high-and very-low-intensity exercise [21][22][23]. Of note, the increased ECS activity induced by exercise was positively correlated with the beneficial antidepressant effects of exercise at central as well as peripheral levels including sense of well-being, anxiety reduction, postexercise calm, and reduced pain sensation [20,[23][24][25][26]. Interestingly, Hill et al. found that augmentation of exercise-induced increase of endocannabinoid tone suppresses stress-associated behaviors and promotes hippocampal cell proliferation, in a manner dependent on stimulation of CB1 stimulation [27,28]. ...
... Physical exercise doubled levels of AEA in healthy volunteers completing an exercise protocol. 21 In 10 healthy nonobese men and women, AEA was observed to substantially increase after a 30-min treadmill test maintaining 72% and 82% of calculated maximal heart rate respectively, although this marked increase in plasma AEA was not seen in the high-intensity exercise group who maintained 92% maximal heart rate for 30 min. 22 Overall circulating endocannabinoid levels were higher in the 72% maximal heart rate group compared with the remaining groups. ...
The societal burden of ischemic stroke suggests a need for additional therapeutic categories in stroke prevention. Modulation of the endocannabinoid system (ECS) is a rational target for stroke prevention because of its effects on inflammation, vascular tone, and metabolic balance, all well-described stroke risk factors. In this article, we summarize the existing ECS clinical studies in human subjects' research as they relate to conventional vascular risk factors associated with ischemic stroke. To date, 2-arachidonoylglycerol (2-AG) derivative endocannabinoids are consistently reported to be elevated in insulin resistance, whereas the N-arachidonoylethanolamine (AEA) endocannabinoid derivatives are elevated in obesity. The ECS role in metabolic health should examine the effects of 2-AG reduction and AEA augmentation as a means of stroke risk reduction. Cannabinoid receptors are reported on macrophages within atherosclerotic plaques and suggest a role for immunomodulation as a therapeutic for atherosclerosis through both peripheral immune cell CB1 antagonism and/or CB2 agonist. The effects of ECS on hypertension, smoking, physical activity, obstructive sleep apnea, heart failure, and atrial fibrillation are incompletely described and deserve further study. A limitation to ECS research is significant overlap with noncannabinoid molecular targets. Further exploration of the ECS needs to include the larger metabolomics context for a greater understanding of its therapeutic potential. Clinical translational studies in stroke prevention should be directed at ECS in metabolic balance and atherosclerosis.
... Other studies have further demonstrated the close relationship between the intensity and type of physical exercise and ECS activity. In particular, while an exercise of moderate intensity was confirmed to increase the plasma levels of AEA in human volunteers, surprisingly no changes in plasma ECs were observed following a very-high-and very-low-intensity exercise [21][22][23]. Of note, the increased ECS activity induced by exercise was positively correlated with the beneficial antidepressant effects of exercise at central as well as peripheral levels including sense of well-being, anxiety reduction, postexercise calm, and reduced pain sensation [20,[23][24][25][26]. Interestingly, Hill et al. found that augmentation of exercise-induced increase of endocannabinoid tone suppresses stress-associated behaviors and promotes hippocampal cell proliferation, in a manner dependent on stimulation of CB1 stimulation [27,28]. ...
The scientific community uses the term endocannabinoid system (ECS) to refer to a large group of molecules that in our body control the production and function of the two major cannabinoid lipid mediators, namely, anandamide (AEA) and 2-arachidonoylglycerol (2-AG). Following their discovery, an impressive number of studies have shown that both AEA and 2-AG play a key role in a large plethora of functions in living organisms. Consequently, functional impairment or dysregula-tion of AEA and 2-AG activity leads to a variety of disorders affecting the nervous system as well as peripheral organs and tissues. For this reason, cannabinoids and/ or cannabinoid synthetic drugs currently represent an important area of research for their potential therapeutic use to treat many human diseases having or not a genetic component. Despite these evidences, the role of the endocannabinoid system and hence potential changes in its activity in inherited muscular dystrophies remains largely unknown. Only recently, the role of endocannabinoid CB1 receptors was identified in Duchenne's muscular dystrophy (DMD). In this chapter, I summarize the chemical properties and functional role of the endocannabinoids as well as plant-derived cannabinoids during skeletal muscle formation and repair under physiological conditions as well as DMD.
... Reports of the effects of exercise on circulating 2-AG concentrations have been less consistent. The early research in this area had not found significant elevations in 2-AG after exercise (43)(44)(45)(46), but more recent research with larger sample sizes have reported elevations in 2-AG after exercise (25,26,47), and weak-to-moderate correlations between changes in 2-AG and improvements in mood. For example, Brellenthin et al. (25) found increases in AEA and 2-AG after moderate-and preferred-intensity treadmill exercise in healthy college-age men and women, which were associated with improvements in mood states, including depression, tension, total mood disturbance and vigor. ...
The endocannabinoid (eCB) system is implicated in the pathophysiology of depression and is responsive to acute exercise in healthy adults.
Purpose:
We aimed to describe acute changes in serum eCB across a prescribed moderate (MOD) and a self-selected/preferred (PREF) intensity exercise session in women with major depressive disorder (MDD) and determine relationships between changes in eCB and mood states.
Methods:
Women with MDD (n = 17) exercised in separate sessions for 20 min on a cycle ergometer at both MOD or PREF in a within-subjects design. Blood was drawn before and within 10 min after exercise. Serum concentrations of eCB (anandamide [AEA], 2-arachidonoylglycerol) and related lipids (palmitoylethanolamine, oleoylethanolamine, 2-oleoylglycerol) were quantified using stable isotope-dilution, liquid chromatography/mass spectrometry/mass spectrometry. The profile of mood states and state-trait anxiety inventory (state only) were completed before, 10 min and 30 min postexercise.
Results:
Significant elevations in AEA (P = 0.013) and oleoylethanolamine (P = 0.024) occurred for MOD (moderate effect sizes: Cohen's d = 0.58 and 0.41, respectively). Significant (P < 0.05) moderate negative associations existed between changes in AEA and mood states for MOD at 10 min (depression, confusion, fatigue, total mood disturbance [TMD] and state anxiety) and 30 min postexercise (confusion, TMD and state anxiety). Significant (P < 0.05) moderate negative associations existed between 2-arachidonoylglycerol and mood states at 10 min (depression and confusion) and 30 min postexercise (confusion and TMD). Changes in eCB or related lipids or eCB-mood relationships were not found for PREF.
Conclusion:
Given the broad, moderate-strength relationships between improvements in mood states and eCB increases after MOD, it is plausible that the eCB system contributes to the mood-enhancing effects of prescribed acute exercise in MDD. Alternative mechanisms are likely involved in the positive mood state effects of preferred exercise.
... The endocannabinoid AEA, however, was highly increased inflight, demonstrating a biological stress response to the environment aboard the ISS. The ECS is an important stress response system and has multiple roles in a myriad of physiological processes of stress (Chouker et al., 2010;Dlugos et al., 2012;Hauer et al., 2013;Neumeister et al., 2015), metabolism (Campolongo et al., 2009), sleep and activity patterns (Richard et al., 2009;Feuerecker et al., 2012). Most importantly, endocannabinoids are potent immune modulators (Sardinha et al., 2014;Buchheim et al., 2018). ...
Space flight exerts a specific conglomerate of stressors on humans that can modulate the immune system. The mechanism remains to be elucidated and the consequences for cosmonauts in the long term are unclear. Most of the current research stems from short-term spaceflights as well as pre- and post-flight analyses due to operational limitations. Immune function of 12 cosmonauts participating in a long-duration (>140 days) spaceflight mission was monitored pre-, post-, and on two time-points in-flight. While the classical markers for stress such as cortisol in saliva where not significantly altered, blood concentrations of the endocannabinoid system (ECS) were found to be highly increased in-flight indicating a biological stress response. Moreover, subjects showed a significant rise in white blood cell counts. Neutrophils, monocytes and B cells increased by 50% whereas NK cells dropped by nearly 60% shortly after landing. Analysis of blood smears showed that lymphocyte percentages, though unchanged pre- and post-flight were elevated in-flight. Functional tests on the ground revealed stable cellular glutathione levels, unaltered baseline and stimulated ROS release in neutrophils but an increased shedding of L-selectin post-flight. In vitro stimulation of whole blood samples with fungal antigen showed a highly amplified TNF and IL-1β response. Furthermore, a significant reduction in CD4+CD25+CD27low regulatory T cells was observed post-flight but returned to normal levels after one month. Concomitantly, high in-flight levels of regulatory cytokines TGF-β, IL-10 and IL-1ra dropped rapidly after return to Earth. Finally, we observed a shift in the CD8+ T cell repertoire toward CD8+ memory cells that lasted even one month after return to Earth. Conclusion: Long-duration spaceflight triggered a sustained stress dependent release of endocannabinoids combined with an aberrant immune activation mimicking features of people at risk for inflammation related diseases. These effects persisted in part 30 days after return to Earth. The currently available repertoire of in-flight testing as well as the post-flight observation periods need to be expanded to tackle the underlying mechanism for and consequences of these immune changes in order to develop corresponding mitigation strategies based on a personalized approach for future interplanetary space explorations.
... One of the most common conditions for challenging human physiological systems is exercise. Although several studies have been done on the role of exercise and its effects on various systems, such as the catecholamine system 1 or the hypothalamic-pituitary axis (HPA) 2 , few studies have examined the role of endocannabinoid system under stressful conditions 3 . Recent researches on human and animal models confirm the strong role of exercise in endocannabinoid system and physiological mechanisms that may eventually lead to "runners high" [4][5] . ...
The aim of this study was investigated the effect of eight weeks of aerobic, anaerobic and resistance training on some endocannabinoid, serotonin, beta-endorphin and BDNF agents of young men. Thirty-two young men (19 to 25 years old) who did not have regular physical activity were randomly divided into four groups, and each of them were participated in various sports exercises for eight weeks. A group for aerobic exercises (two exercises with 65-70 maximum heart rate 3 sessions per week), an anaerobic exercise group (two exercises with a maximum intensity of 3 sessions per week), a group for circular resistance exercises (6-8 Station Which is repeated 8-12 times, and for three times a week) and finally a group was selected as a control. ELISA method was used to measure endocannabinoid system, serotonin, beta-endorphin and BDNF factors. The results showed that eight weeks aerobic training significantly increased serotonin levels and eight weeks aerobic and anaerobic exercise significantly increased BDNF. Aerobic, anaerobic, and resistive exercises have no significant effect on arachidonoyl glycerol (2-AG), anandamide(AEA) and beta-endorphin. There was a significant increase in happiness in all three training groups compared to the control group.The results of this study indicated an increase in mediation associated with pleasure and happiness in humans. Concerning the particular effect of long-term exercise on the endocannabinoid system, it is difficult to conclude.
... There is no extensive literature on the role of the NAEs nor endocannabinoids in conditions of HA hypoxia, especially in HA natives. An activation of the ECS has been reported in athletes suddenly exposed to HA (Feuerecker et al., 2012). OEA plays a specific role in sleep apnea, not only is it higher in patients suffering the disease but OEA levels also correlate with respiratory distress index ( Jumpertz et al., 2010), which is a key component in high-altitude (HA) pulmonary edema. ...
Alarcón-Yaquetto, Dulce E., Lidia Caballero, and Gustavo F. Gonzales. Association between plasma N-acylethanolamides and high hemoglobin concentration in Southern Peruvian highlanders. High Alt Med Biol 00:000-000, 2017.-High-altitude (HA) hypoxia is a stressful condition endured by organisms through different mechanisms. Failing to adapt to chronic HA exposure leads to a disease called chronic mountain sickness (CMS) characterized by excessive erythrocytosis (hemoglobin [Hb] ≥19 g/dL for women and ≥21 g/dL for men). Genes encoding for peroxisome proliferator-activated receptor (PPAR) subunits α and γ have been proposed as candidate genes for HA adaptation. N-acylethanolamides (NAEs) are endogenous fatty acid substances that bind to PPAR-α and -γ. NAEs are also able to modulate the endocannabinoid system, a signaling pathway activated in physiological stressful conditions. In the frame of a metabolomic study, we measured plasma levels of four NAEs: palmitoylethanolamide (PEA), oleoylethanolamide (OEA), stearoyl ethanolamide (SEA), and linoleoyl ethanolamide (LEA) in natives from Puno (3830 m), a city located in the Peruvian Southern Andes, and Lima (150 m). All NAEs were significantly higher in the HA population (p < 0.001, q < 0.001). Subjects with higher NAE values were those with higher Hb concentration and lower pulse oxygen saturation. However, there was no association between NAEs and CMS score. Our results suggest that PEA and OEA could be involved in physiological regulation following long-term HA exposure.
... walking) nor nearmaximal intensities of exercise affected AEA concentrations (Raichlen et al, 2012;Raichlen et al, 2013) suggesting a "U-shaped" relationship between exercise and AEA mobilization. Well-trained healthy volunteers who participated in a "strenuous" hike at altitude below 2100 m and those who hiked and ascended approximately 2000 meters in altitude both exhibited significant increases in circulating AEA concentrations following the exercise period (Feuerecker et al, 2012b). Interestingly, hypoxic stress of exercise at high altitude appeared to potentiate the increase in AEA in this study. ...
The goal of this review is to summarize studies in which concentrations of circulating endocannabinoids in humans have been examined in relationship to physiological measurements and pathological status. The roles of endocannabinoids in the regulation of energy intake and storage have been well studied and the data obtained consistently support the hypothesis that endocannabinoid signaling is associated with increased consumption and storage of energy. Physical exercise mobilizes endocannabinoids, which could contribute to refilling of energy stores and also to the analgesic and mood-elevating effects of exercise. Circulating concentrations of 2-arachidonoylglycerol are very significantly circadian and dysregulated when sleep is disrupted. Other conditions under which circulating endocannabinoids are altered include inflammation and pain. A second important role for endocannabinoid signaling is to restore homeostasis following stress. Circulating endocannabinoids are stress-responsive and there is evidence that their concentrations are altered in disorders associated with excessive stress, including post-traumatic stress disorder. Although determination of circulating endocannabinoids can provide important information about the state of endocannabinoid signaling and thus allow for hypotheses to be defined and tested, the large number of physiological factors that contribute to their circulating concentrations makes it difficult to use them in isolation as a biomarker for a specific disorder.Neuropsychopharmacology accepted article preview online, 27 June 2017. doi:10.1038/npp.2017.130.
... With the exception of Cedernaes et al. (2016), previous studies employing aerobic exercise have reported non-significant increases in circulating 2-AG. Data from a few of these studies indicated that there were medium to large effect size increases(14, 41) or an observable trend for increases in 2-AG after exercise(50). ...
Purpose:
To examine eCB and mood responses to prescribed and preferred exercise among individuals with low, moderate, and high levels of physical activity.
Methods:
Thirty-six healthy adults (21±4yrs) were recruited from low (≤60min moderate-vigorous physical activity [MVPA]/wk), moderate (150-299min MVPA/wk), and high (≥300 MVPA/wk) physical activity groups. Participants performed both prescribed (approx. 70-75% max) and preferred (i.e., self-selected) aerobic exercise on separate days. Mood states and eCB concentrations were assessed before and after exercise conditions.
Results:
Both preferred and prescribed exercise resulted in significant increases (p < 0.01) in circulating eCBs (AEA, 2-AG); however, increases in AEA (p < 0.05) were larger in the prescribed condition. Likewise, both preferred and prescribed exercise elicited positive mood improvements compared to pre-exercise values, but changes in state anxiety, total mood disturbance, and confusion were greater in the preferred condition (p < 0.05). Changes in 2-AG concentrations were found to negatively correlate with changes in depression, tension, and total mood disturbance in the preferred condition (p < 0.05), and changes in AEA were positively associated with changes in vigor in the prescribed condition (p < 0.05). There were no significant group differences for mood or eCB outcomes.
Conclusion:
These results indicate that eCB and mood responses to exercise do not differ significantly between samples with varying physical activity levels. This study also demonstrates that in addition to prescribed exercise, preferred exercise activates the eCB system, and this activation may contribute to positive mood outcomes with exercise.
The complex of space flight (SF) factors can have a negative impact on the human organism, including the innate and adaptive immunity. One of the negative effects of impaired functional activity of the immune system is a decrease of latent infections immunological control. During short- and long-term SF, reactivation of latent viruses was shown, while the virus was detected in body fluids for some time after returning to Earth. Despite the fact that in most cases reactivation was asymptomatic, there are fears that during long expeditions into deep space, reactivation of latent pathogens can lead to the development of diseases that are dangerous to the crewmembers health. There is a lot of data about the viral pathogens reactivation in SF, but the reactivation of bacterial agents in cosmonauts has received almost no attention. Due to the complexity of conducting research in space, an important role is played by ground-based analog experiments that simulate the space station conditions. One of the most significant analogues of SF is the long-term Antarctic expedition, which makes it possible to obtain unique information about the effect of isolation, increased mental and physiological stress on the latent pathogens reactivation. Currently, latency is increasingly considered as a symbiotic existence of a pathogen and host, during which the human body acquires additional resistance to certain infectious agents. Thus, an important task of the upcoming research is a comprehensive analysis of the personal immunological status in the SF, establishing its relationship with the latent infections reactivation and developing systems for monitoring, preventing and treating the negative consequences of reactivation.
Acute aerobic exercise improves mood and activates the endocannabinoid (eCB) system in physically active individuals; however, both mood and eCB responses to exercise may vary based on habitual levels of physical activity.
Purpose
This study aimed to examine eCB and mood responses to prescribed and preferred exercises among individuals with low, moderate, and high levels of physical activity.
Methods
Thirty-six healthy adults (21 ± 4 yr) were recruited from low (≤60 min moderate–vigorous physical activity [MVPA] per week), moderate (150–299 min MVPA per week), and high (≥300 MVPA per week) physical activity groups. Participants performed both prescribed (approximately 70%–75% max) and preferred (i.e., self-selected) aerobic exercise on separate days. Mood states and eCB concentrations were assessed before and after exercise conditions.
Results
Both preferred and prescribed exercise resulted in significant increases ( P < 0.01) in circulating eCB ( N -arachidonoylethanolamine [AEA] and 2-arachidonoylglycerol); however, increases in AEA ( P < 0.05) were larger in the prescribed condition. Likewise, both preferred and prescribed exercise elicited positive mood improvements compared with preexercise values, but changes in state anxiety, total mood disturbance, and confusion were greater in the preferred condition ( P < 0.05). Changes in 2-arachidonoylglycerol concentrations were found to negatively correlate with changes in depression, tension, and total mood disturbance in the preferred condition ( P < 0.05), and changes in AEA were positively associated with changes in vigor in the prescribed condition ( P < 0.05). There were no significant group differences for mood or eCB outcomes.
Conclusion
These results indicate that eCB and mood responses to exercise do not differ significantly between samples with varying physical activity levels. This study also demonstrates that in addition to prescribed exercise, preferred exercise activates the eCB system, and this activation may contribute to positive mood outcomes with exercise.
Cannabinoids (CBDs) represent a group of C21 or C22 terpenophenolic compounds predominantly produced by Cannabis but have also been found in plants from the Radula and Helichrysum genera. There are about 100 different cannabinoids, although some of them are metabolites. They are generally classified into ten subclasses [1–3].
Studies in recent years have shown that the endocannabinoid (eCB) system is activated by exercise and modulates several physiological processes. Thus, the present review aimed to summarize the literature about the involvement of the eCB system in the control of pain, obesity, and metabolism by exercise. MEDLINE, EMBASE, and Web of Science were searched for experimental studies that investigated the presence of the eCB system in animal models of pain and obesity, in which the animals were subjected to different exercise modalities. The primary outcomes were pain, obesity, and metabolism. The databases were searched for articles from their inception up until March 2020. Two independent reviewers extracted the data and assessed the methodological quality of the included studies. Thirteen studies were considered eligible for this review. The results indicated that there was increased expression and levels of cannabinoid receptors and eCBs, respectively, after aerobic and resistance exercise, and that this effect was associated with antinociception. The eCB system was modulated by exercise in obese rats, confirming that it may also be involved in the control of obesity and metabolism when these are modulated by aerobic training. Exercise can be effective in controlling pain, partly through the involvement of the eCB system. In addition, exercise can modulate the imbalance of the eCB system in obesity and metabolic disorders, thus also controlling these pathologies through this signaling system.
Anandamide (AEA) is a fatty acid neurotransmitter that binds to the CB1 and CB2 cannabinoid receptors in the central and peripheral nervous systems. AEA functions with the dopaminergic system and its expression has been shown to increase during activity. Cannabinoids have been used as treatments to reduce pain and discomfort, so an increase in AEA during activity may have a similar function. To determine the effects of AEA on energy expenditure, behavioral changes after exposure to AEA were observed in adult zebrafish (Danio rerio). The fish were separated into 4 groups: low dose AEA (10 M), high dose AEA (100 M), a purported positive control (0.5% ethanol), and a negative control (untreated). Activity was measured by counting the number of times an individual fish crossed a horizontal or vertical line drawn on the aquarium using 5-min recorded intervals (line breaks). Vertical line breaks were significantly different between the untreated group and both of the AEA-treated groups (p < 0.0001), however horizontal line breaks were not significantly different (p = 0.14). An increase in the number of vertical line crossings indicate that the fish in both AEA groups were swimming along the horizontal plane more often than the other groups, indicating an increase in physical activity. There was no difference in the activity of the ethanol-treated group compared to the untreated group. These results demonstrate that the administration of a cannabinoid agonist such as AEA may increase overall activity levels in adult zebrafish.
Background
Plasma levels of the major endocannabinoids 2-arachidonoylgycerol (2AG) and anandamide (N-arachidonoylethanolamine, AEA) have been identified to vary independently with particular pathological conditions. The levels of these endocannabinoids are tightly regulated by two hydrolytic enzymes, monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), respectively.
Objectives
In this study, we have quantified these enzyme activities in the major blood fractions.
Patients/Methods
In blood fractions from human volunteers, radiometric assays were used to quantify monoacylglycerol lipase and fatty acid amide hydrolase. Tagging with fluorophosphonate-rhodamine allowed quantification of platelet serine hydrolase activities.
Results
Fatty acid amide hydrolase activity was highest in platelets, while MAGL activity was most abundant in erythrocytes. Sampling the blood of donors on two further occasions 15 days apart showed no significant change in platelet FAAH or erythrocyte MAGL activities. Activities were not different when comparing female donors with males. Storage of these blood fractions at -80 °C was associated with a rapid loss in enzyme activities, which could largely by avoided by storage in liquid nitrogen. Incubation of platelets and erythrocytes in the presence of thrombin lead to release of measurable FAAH, but not MAGL, activity. Tagging of serine hydrolase activities with fluorophosphonate-rhodamine allowed confirmation of MAGL activity in platelet preparations, as well as multiple other enzymes.
Conclusions
These investigations suggest a potential role for FAAH in regulation of coagulation, while the role of MAGL in blood requires further investigation.
Chronic pain states are highly prevalent and yet poorly controlled by currently available analgesics. It has been reported that enriched environment (EE), as a new way of endogenous pharmacotherapy, is effective in attenuating chronic inflammatory pain. However, the underlying molecular mechanisms are still not fully understood. NMDA NR2B receptor plays a critical role in pain transmission and modulation. Thus, in this study, we aimed at the effect of EE on the NR2B receptors expression in the prefrontal cortex, hippocampus and thalamus in the inflammatory pain mice. The results showed a significant increase of NR2B receptors in the thalamus of mice at 7 d following injection of CFA in the subcutaneous of the bottom of the left hind paw. EE significantly reduced the duration of mechanical hypersensitivity and anxiety-related behavior and the expression of NR2B receptors as compared to the standard condition. Furthermore, EE significantly increased 2-arachidonoylglycero (2-AG) levels at 7 d in the inflammatory pain mice as compared to the standard condition, and the effect of EE on the behavior and the expression of NR2B receptors was abolished by intraperitoneal injection of AM281 (a selective antagonist of CB1 receptor). Elevated 2-AG levels by intraperitoneal injection of JZL184 (a selective inhibitor of MAGL, the enzyme responsible for 2-AG hydrolysis) produced the same effect as EE. Results from this study provide the evidence that EE mimics endocannabinoids to take analgesic and anti-anxiety activities by decreasing the expression of the NR2B receptors via the CB1 receptor in the thalamus, pending further studies.
Low oxygen breathing has been the subject of considerable research in recent years. The present review aims to determine the physiological and neuropsychological benefits of low-oxygen training. Specifically, we explored the ways low oxygen affects hormones, neurotransmitters and growth factors responsible for neuroplasticity, higher cognition and positive emotions. In addition, we shed light on the importance of hypoxia to expand the conscious experience. Furthermore, we investigate the role of digital technologies in assisting hypoxic training. The results showed that, when hypoxia occurs, the human body puts into action the amazing survival mission which reveals unexplored alternative plans and healing pathways. Oxygen deprivation, under certain circumstances, has beneficial effects on cognition, mood and consciousness. It was observed an increase in growth factors, which are responsible for tissue repair and regeneration. Hypoxia also was found to stimulate the hormones of pleasure, happiness, pain tolerance, socialization and relaxation. Interestingly, people under hypoxic conditions are more likely to have transcendental experiences-even to develop 'superhuman' abilities. Digital technologies facilitate the safe implementation of hypoxic training enabling users to take control of a powerful tool, which is none other than breathing. Metacognition in breathing can help people consciously and safely manipulate their breathing by moving themselves away from their comfort zone and exploring new pathways to rewire their brains and plumb the depths of their physical, cognitive, emotional and spiritual potential. Our findings suggest that hypoxic training could be an effective intervention strategy with important therapeutic benefits for people with learning and other disabilities (i.e adhd, memory deficits, autism, motor, impairments, depression, generalized anxiety disorder). Future educators, therapists and families should be trained to appropriate apply simple hypoxic training exercises even in the educational context. For that reason, research into the physiological and neuropsychological mechanism that is affected by hypoxic training for individuals with learning or other disabilities is necessary.
The runner’s high is an ephemeral feeling some humans experience during and after endurance exercise. Recent evidence in mice suggests that a runner’s high depends on the release of endocannabinoids (eCBs) during exercise. However, little is known under what circumstances eCBs are released during exercise in humans. This systematic review sampled all data from clinical trials in humans on eCB levels following exercise from the discovery of eCBs until April 20, 2021. PubMed/NCBI, Ovid MEDLINE, and Cochrane library were searched systematically and reviewed following the PRISMA guidelines. From 278 records, 21 met the inclusion criteria. After acute exercise, 14 of 17 studies detected an increase in eCBs. In contrast, after a period of long-term endurance exercise, four articles described a decrease in eCBs. Even though several studies demonstrated an association between eCB levels and features of the runner’s high, reliable proof of the involvement of eCBs in the runner’s high in humans has not yet been achieved due to methodological hurdles. In this review, we suggest how to advance the study of the influence of eCBs on the beneficial effects of exercise and provide recommendations on how endocannabinoid release is most likely to occur under laboratory conditions.
Background
We aimed to assess the effects of six weeks of resistance training (RT) combined with saffron supplementation on markers implicated in depression as well as happiness levels in untrained young males.
Materials and methods
Untrained young male participants were randomly assigned to one of two groups: RT + saffron supplement (RS; n = 14) or RT + placebo (RP; n = 14). For 6 weeks, participants in the RS group took one 150 mg pill of pure saffron immediately after each RT session and at the same time on non-training days. Those assigned to the RP group took a dextrose pill. Concentrations of Anandamide (AEA), 2-Arachidonoylglycerol (2-AG), serotonin, dopamine, β-endorphin (beta-endorphin), tryptophan, happiness levels (via questionnaire), and body composition were assessed before and after the 6 weeks of whole-body supervised RT (4x/week, 3 sets using 60-70% of 1-repetition maximum [1-RM]).
Results
AEA (0.5 ng/ml), 2-AG (0.04 ng/ml), dopamine (0.7 ng/ml), and β-endorphin (9.4 pg/ml) concentrations significantly increased in the RS group (P<0.05) while no changes were detected in the RP group. Serotonin (RS = 0.5 ng/mL and RP = 0.09 ng/mL) concentrations and happiness levels significantly increased in both groups with greater changes in RS group while tryptophan concentrations remained unchanged (P> 0.05). In addition, both groups significantly increased muscular endurance with greater changes in RS group (P<0.05).
Conclusion
Six weeks of RT combined with saffron supplementation improved AEA, 2-AG, dopamine, β-endorphin, and serotonin concentrations. Moreover, the addition of saffron supplement to chronic RT results in greater improvements in happiness levels than RT alone.
Aging is associated with changes in hormones, slowing of metabolism, diminished physiological processes, chronic inflammation and high exposure to oxidative stress factors, generally described as the biological cost of living. Lifestyle interventions of diet and exercise can improve the quality of life during aging and lower diet-related chronic disease. The endocannabinoid system (ECS) has important effects on systemic metabolism and physiological systems, including the central and peripheral nervous systems. Exercise can reduce the loss of muscle mass and improve strength, and increase the levels of endocannabinoids (eCB) in brain and blood. Although the ECS exerts controls on multiple systems throughout life it affords benefits to natural aging. The eCB are synthesized from polyunsaturated fatty acids (PUFA) and the primary ones are produced from arachidonic acid (n-6 PUFA) and others from the n-3 PUFA, namely eicosapentaenoic and docosahexaenoic acids. The eCB ligands bind to their receptors, CB1 and CB2, with effects on appetite stimulation, metabolism, immune functions, and brain physiology and neuroplasticity. Dietary families of PUFA are a primary factor that can influence the types and levels of eCB and as a consequence, the downstream actions when the ligands bind to their receptors. Furthermore, the association of eCB with the synthesis of oxylipins (OxL) is a connection between the physiological actions of eCB and the lipid derived immunological OxL mediators of inflammation. OxL are ubiquitous and influence neuroinflammation and inflammatory processes. The emerging actions of eCB on neuroplasticity, well-being and pain are important to aging. Herein, we present information about the ECS and its components, how exercise and diet affects specific eCB, their role in neuroplasticity, neuroinflammation, pain, mood, and relationship to OxL. Poor nutrition status and low nutrient intakes observed with many elderly are reasons to examine the role of dietary PUFA actions on the ECS to improve health.
As exercise intervention solely for pain reduction is relatively new, the available research still leaves an incomplete picture of responsible mechanisms and pathways. Nonetheless, evidence indicates that exercise‐induced analgesia involves activation of the endocannabinoid (eCB) system. The present study investigated the role of the eCB system on the antihyperalgesic effect of high‐intensity swimming exercise (HISE) in an animal model of peripheral persistent inflammation. Male Swiss mice were allocated to non‐exercised and exercised groups and subjected to subcutaneous intraplantar injection (i.pl.) of a single dose of complete Freund's adjuvant (CFA) to induce inflammatory pain. Cumulative HISE was performed once a day and mechanical hyperalgesia and edema were evaluated 0.5h after HISE for seven consecutive days. To investigate the role of the eCB system on the antihyperalgesic effect of HISE, non‐exercised and exercised mice, received intraperitoneal (i.p.), intrathecal (i.t.) or i.pl. injections of vehicle, AM281 (a CB1 cannabinoid receptor antagonist) or AM630 (a CB2 cannabinoid receptor antagonist) from the 3rd to 5th day after CFA injection. Mechanical hyperalgesia was evaluated 0.5h after HISE. In addition, the effect of the fatty acid amide hydrolase [FAAH] inhibitor or monoacylglycerol lipase [MAGL] inhibitor on the antihyperalgesic action of HISE was investigated. HISE reduced mechanical hyperalgesia with effects prevented by AM281 or AM630 pretreatment in all delivery routes tested. The inhibition of FAAH and MAGL prolonged the antihyperalgesic effect of HISE. These data demonstrate evidence for the role of the eCB system upon exercise induced analgesia in a murine model of inflammatory pain.
From Bud to Brain: A Psychiatrist's View of Marijuana - by Timmen L. Cermak April 2020
The endocannabinoid system (ECS) is an old and evolutionarily well preserved neurobiologic system controlling some key elements of organ homeostasis. In contrast to its long biologic history, the scientific record of the ECS is very short. Whereas the occurrence of genes for the endocannabinoid receptors has been described in ancient animals reaching at least as far back as the predecessor of tetrapods (amphibians reptiles, birds, and mammals), modern science has only more recently demonstrated that the ECS is involved in the regulation of a wide range of essential central and peripheral processes which include metabolism and feeding behavior, inflammatory- and anti-inflammatory immunologic reactions, neurobehavioral changes during stress and anxiety and the regulation of central functions such as cognition and memory. One of the most important roles of the ECS lies in the regulation and orchestration of the central and immunologic stress response to aversive and threatening life conditions. There are already data that the ECS is affected in humans during highly aversive conditions of parabolic flights and space flights as well as in other extreme living conditions (e.g. Antarctica). The ECS may therefore have an important function for adaption processes in such aversive conditions.
Humans subjected to hostile environments are more prone and vulnerable to infections due to the complex interaction of various stressors. Besides other mechanisms known to induce immune imbalance and suppression as described in this book, this chapter focuses on the still very little known role of hypoxia-triggered immunosuppressive mechanisms in astronauts/cosmonauts e.g. during long-duration space missions. Such hypoxia signaling-dependent pathways might act additionally to those stimulated by neurohumoral mediators of the stress response even in the absence of hypoxia i.e. under normoxia. Altogether, hypoxic and normoxic pathways of the neurohumoral stress response may synergistically result in immune dysfunctional states, also pending on the duration of exposition. The role of hypoxia is of emerging interest to spaceflight, since hypobaric living conditions and hypoxemic tissue perfusion are not unlikely to occur in the future of human space exploration as due to technical and operational needs.
Background and Objectives: One of the most common challenges for human physiological system is exercise.
Therefore, the aim of this study was determining the effect of different types of exercise on endocannabinoid system agents such as anandamide (AEA) and 2-arsidonyl glycerol (2-AG).
Materials and Methods: In this clinical trial study, 32 young men (19-25 years old) volunteered from among students of Islamic Azad University of Babol, who did not have any regular sports activities. They were randomly divided into four groups of eight persons. After having the same breakfast, the subjects’ blood were taken before and after short time aerobic exercise (running training with oxigen consumption of 70% of maximal
heart rate until full exhaustion), anaerobic exercise (running training with maximum intensity until full exhaustion) and resistance exercise (with 8 stations until full exhaustion). The control group did not do any exercise. The anandamide and 2-arsidonyl glycerol factors were evaluated by ELISA method. Data were analyzed using ANOVA, ANCOVA and paired t-test method.
Results: The results of this study showed that short time aerobic, anaerobic and resistance exercise did not have any significant effect on endocannabinoid system factors (p> 0.05).
Conclusion: The results of this study showed that endocannabinoid system is not affected by different training methods until exhaustion.
Physical activity is an important lifestyle factor for growth, development, and sustained health throughout life. In recent years, the benefits of physical activity have drawn more attention to its physiological effects on the body, including well-being. The endocannabinoid system (ECS) has emerged as a focal point to ascertain the mechanisms for how exercise benefits the body and how it reduces or controls pain. The ECS, its ligands [the endocannabinoids (eCB)], receptors (CB1 and CB2), enzymes for the synthesis and degradation of eCB, and the polyunsaturated fatty acids (PUFA) that serve as substrates, comprise a powerful biological organization of multiple controls that affects mood, inflammation, pain, and other neurological aspects of the central nervous system and peripheral nervous system. Recently, investigators have reported increases in circulating levels of eCB after exercise, with some eCB exerting analgesic effects from exercise. The focus of this review is to discuss evidence for the role of eCB and the complexities of the ECS in exercise and pain. Some aspects presented herein are production of eCB and activation of the cannabinoid receptors in the brain following exercise; eCB, pain, and physical activity; oxylipins; and joint pain. Future research on the ECS must include mechanistic approaches to endocannabinoid signaling and explain the role of dietary PUFA in altering signaling of the receptors that affects pain. Additionally, how other types of exercise, such as Tai Chi, which is reported to improve well-being, should be investigated to ascertain if changes in eCB mediate the mind and body benefits of Tai Chi. As we age, exercise in the form of play has evolved with the exploration of our body from walking to running, recreational, and competitive sports, to midlife physical activity focusing on maintaining fitness and a healthy body weight. Furthermore, exercise has been a target of investigation to explore various hypotheses to explain the mechanisms for cognitive benefits in the young and in older adults. The science of exercise has matured to a level of importance in the life cycle to reduce pain with aging and include new investigations on the ECS to explain its role in well-being and improved quality of life in later years.
Endocannabinoids (ECs) control metabolism via cannabinoid receptors type 1 (CB1). Their plasma levels are elevated in overweight type 2 diabetes (T2D) and in obese patients, and decrease postprandially in normoweight individuals. We investigated in two different cohorts of nonobese or obese volunteers whether oral glucose in glucose tolerance tests (OGTT) or acute insulin infusion during euglycemic hyperinsulinemic clamp affect plasma EC levels.
OGTT was performed in ten obese hyperinsulinemic patients (body mass index (BMI)=35.8 kg/m2, fasting insulin=14.83 mU/l), and ten normoweight normoinsulinemic volunteers (BMI=21.9 kg/m2, fasting insulin=7.2 mU/l). Insulin clamp was performed in 19 mostly nonobese men (BMI=25.8 kg/m2) with varying degrees of liver fat and plasma triglycerides (TGs), with (n=7) or without T2D. Plasma levels of ECs (anandamide and 2-arachidonoylglycerol (2-AG)) were measured by liquid chromatography-mass spectrometry, before and 60 and 180 min after OGTT, and before and 240 and 480 min after insulin or saline infusion.
Oral glucose load decreased anandamide plasma levels to an extent inversely correlated with BMI, waist circumference, subcutaneous fat, fasting insulin and total glucose, and insulin areas under the curve during the OGTT, and nonsignificantly in obese volunteers. Insulin infusion decreased anandamide levels to an extent that weakly, but significantly, correlated negatively with TGs, liver fat and fasting insulin, and positively with high density lipoprotein cholesterol. OGTT decreased 2-AG levels to a lower extent and in a way weakly inversely correlated with fasting insulin.
We suggest that insulin reduces EC levels in a way inversely related to anthropometric and metabolic predictors of insulin resistance and dyslipidemia.
To test the hypothesis of whether strenuous physical exercise inhibits neutrophils that can get activated by hypobaric hypoxia, we analyzed the effects of both high altitude and strenuous exercise alone and in combination on potentially cytotoxic functions of granulocytes in healthy volunteers (n = 12 men; average age 27.6 yr; range 24-38 yr). To this end, a field study was prospectively performed with an open-labeled within-subject design comprising three protocols. Protocol I (high altitude) involved a helicopter ascent, overnight stay at 3,196 m, and descent on the following day. Protocol II (physical exercise) involved hiking below an altitude of 2,100 m with repetitive ascents amounting to a total ascent to that of protocol III. Protocol III (combination of physical exercise and high altitude) involved climbing from 1,416 to 3,196 m, stay overnight, and descent on the following day. In protocol I, number of granulocytes did not change, but potentially cytotoxic functions of cells (CD18 expression and superoxide production) were early and significantly upregulated. In protocol II, subjects developed granulocytosis, but functions of cells were inhibited. In protocol III, granulocytosis occurred at higher values than those observed under protocol II. Potentially cytotoxic functions of cells, however, were strongly inhibited again. In conclusion, high altitude alone, even moderate in extent, can activate potentially cytotoxic functions of circulating granulocytes. Strenuous physical exercise strongly inhibits this activation, which may give protection from an otherwise inflammatory injury.
Acute stress suppresses pain by activating brain pathways that engage opioid or non-opioid mechanisms. Here we show that an opioid-independent form of this phenomenon, termed stress-induced analgesia, is mediated by the release of endogenous marijuana-like (cannabinoid) compounds in the brain. Blockade of cannabinoid CB(1) receptors in the periaqueductal grey matter of the midbrain prevents non-opioid stress-induced analgesia. In this region, stress elicits the rapid formation of two endogenous cannabinoids, the lipids 2-arachidonoylglycerol (2-AG) and anandamide. A newly developed inhibitor of the 2-AG-deactivating enzyme, monoacylglycerol lipase, selectively increases 2-AG concentrations and, when injected into the periaqueductal grey matter, enhances stress-induced analgesia in a CB1-dependent manner. Inhibitors of the anandamide-deactivating enzyme fatty-acid amide hydrolase, which selectively elevate anandamide concentrations, exert similar effects. Our results indicate that the coordinated release of 2-AG and anandamide in the periaqueductal grey matter might mediate opioid-independent stress-induced analgesia. These studies also identify monoacylglycerol lipase as a previously unrecognized therapeutic target.
Stress hormones, adrenaline (epinephrine) and noradrenaline (norepinephrine), are responsible for many adaptations both at rest and during exercise. Since their discovery, thousands of studies have focused on these two catecholamines and their importance in many adaptive processes to different stressors such as exercise, hypoglycaemia, hypoxia and heat exposure, and these studies are now well acknowledged. In fact, since adrenaline and noradrenaline are the main hormones whose concentrations increase markedly during exercise, many researchers have worked on the effect of exercise on these amines and reported 1.5 to >20 times basal concentrations depending on exercise characteristics (e.g. duration and intensity). Similarly, several studies have shown that adrenaline and noradrenaline are involved in cardiovascular and respiratory adjustments and in substrate mobilization and utilization. Thus, many studies have focused on physical training and gender effects on catecholamine response to exercise in an effort to verify if significant differences in catecholamine responses to exercise could be partly responsible for the different performances observed between trained and untrained subjects and/or men and women. In fact, previous studies conducted in men have used different types of exercise to compare trained and untrained subjects in response to exercise at the same absolute or relative intensity. Their results were conflicting for a while.
As research progressed, parameters such as age, nutritional and emotional state have been found to influence catecholamine concentrations. As a result, most of the recent studies have taken into account all these parameters. Those studies also used very well trained subjects and/or more intense exercise, which is known to have a greater effect on catecholamine response so that differences between trained and untrained subjects are more likely to appear. Most findings then reported a higher adrenaline response to exercise in endurance-trained compared with untrained subjects in response to intense exercise at the same relative intensity as all-out exercise. This phenomenon is referred to as the ‘sports adrenal medulla’. This higher capacity to secrete adrenaline was observed both in response to physical exercise and to other stimuli such as hypoglycaemia and hypoxia. For some authors, this phenomenon can partly explain the higher physical performance observed in trained compared with untrained subjects. More recently, these findings have also been reported in anaerobic-trained subjects in response to supramaximal exercise. In women, studies remain scarce; the results are more conflicting than in men and the physical training type (aerobic or anaerobic) effects on catecholamine response remain to be specified. Conversely, the works undertaken in animals are more unanimous and suggest that physical training can increase the capacity to secrete adrenaline via an increase of the adrenal gland volume and adrenaline content.
A plausible determinant of the specificity of receptor signaling is the cellular compartment over which the signal is broadcast. In rat heart, stimulation of β1-adrenergic receptor (β1-AR), coupled to Gs-protein, or β2-AR, coupled to Gs- and Gi-proteins, both increase L-type Ca2+ current, causing enhanced contractile strength. But only β1-AR stimulation increases the phosphorylation of phospholamban, troponin-I, and C-protein, causing accelerated muscle relaxation and reduced myofilament sensitivity to Ca2+. β2-AR stimulation does not affect any of these intracellular proteins. We hypothesized that β2-AR signaling might be localized to the cell membrane. Thus we examined the spatial range and characteristics of β1-AR and β2-AR signaling on their common effector, L-type Ca2+ channels. Using the cell-attached patch-clamp technique, we show that stimulation of β1-AR or β2-AR in the patch membrane, by adding agonist into patch pipette, both activated the channels in the patch. But when the agonist was applied to the membrane outside the patch pipette, only β1-AR stimulation activated the channels. Thus, β1-AR signaling to the channels is diffusive through cytosol, whereas β2-AR signaling is localized to the cell membrane. Furthermore, activation of Gi is essential to the localization of β2-AR signaling because in pertussis toxin-treated cells, β2-AR signaling becomes diffusive. Our results suggest that the dual coupling of β2-AR to both Gs- and Gi-proteins leads to a highly localized β2-AR signaling pathway to modulate sarcolemmal L-type Ca2+ channels in rat ventricular myocytes.
Two topics are presented in this review. In the first section, we review data regarding the effects of the endocannabinoids (eCBs) and cannabinoid receptors on neuroimmune function. The function of eCBs in the interaction between the immune system and the central nervous system (CNS) is of particular interest, since the CNS itself is a rich source of eCBs while being exquisitely sensitive to inflammation. There are several sites at which cannabinoids can influence neuroinflammation. Microglial cells express both CB receptors and make eCBs. Activation of CB receptors on these cells seems to promote migration and proliferation but to reduce activation to macrophages. In several neurodegenerative diseases, up-regulation of microglial CB2 receptors have been observed. It is our hypothesis that microglial CB receptor activity is anti-inflammatory and could be exploited to manipulate neuroinflammatory processes with a minimum of unwanted effects. The second topic discussed suggests that the eCB/CB1 receptor pair is involved in the responses of animals to acute, repeated and variable stress. The roles of this pair are complex and dependent upon previous stress, among other things. Dysfunctional responding to stress is a component of several human neuropsychiatric disorders, including anxiety and panic disorders, post-traumatic stress disorders, premenstrual dysphoria and quite possibly, drug abuse. While it is too early to say with certainty, it is very possible that either inhibition or potentiation of endocannabinoid signaling will be an efficacious novel therapeutic approach to more than one human psychiatric disease.
The endocannabinoid system has been recognized as a major neuromodulatory system, which functions to maintain brain homoeostasis. Endocannabinoids are synthesized and released from the postsynapse and act as retrograde neuronal messengers, which bind to cannabinoid type 1 receptors at the presynapse. Here, they inhibit the release of neurotransmitters, including glutamate and GABA. By these means, endocannabinoids control the activation of various neuronal circuits including those involved in neuroendocrine stress processing. Accordingly, exogenous cannabinoids such as the major active component of marijuana, Delta(9)-tetrahydrocannabinol, have long been known to activate the major neuroendocrine stress response system of mammals, the hypothalamic-pituitary-adrenocortical (HPA) axis. However, the function of the endocannabinoid system in the regulation of stress hormone secretion has only recently begun to be understood. It is the focus of the present review to provide the reader with an overview of our current knowledge of the role of endocannabinoid signalling in HPA axis regulation under basal as well as under stressful conditions. This includes the specific sites of action, potential underlying neuronal pathways and interactions between behavioural and neuroendocrine stress coping. Furthermore, the potential role of HPA axis activity dysregulations, caused by deficits in the endocannabinoid system, for the pathophysiology of psychiatric diseases is discussed.
The endocannabinoid system is a neuroactive lipid signaling system that functions to gate synaptic transmitter release. Accumulating evidence has demonstrated that this system is responsive to modulation by both stress and glucocorticoids within the hypothalamus and limbic structures; however, the nature of this regulation is more complex than initially assumed. The aim of the current review is to summarize the research to date which examines the effects of acute stress and glucocorticoid administration on endocannabinoid signaling in limbic-hypothalamic-pituitary-adrenal (LHPA) axis, and in turn the role endocannabinoid signaling plays in the neurobehavioural responses to acute stress and glucocorticoid administration. The majority of research suggests that acute stress produces a mobilization of the endocannabinoid 2-arachidonoylglycerol (2-AG) while concurrently reducing the tissue content of the other endocannabinoid ligand anandamide. Genetic and pharmacological studies demonstrate that the reduction in anandamide signaling may be involved in the initiation of HPA axis activation and the generation of changes in emotional behaviour, while the increase in 2-AG signaling may be involved in terminating the stress response, limiting neuronal activation and contributing to changes in motivated behaviours. Collectively, these studies reveal a complex interplay between endocannabinoids and the HPA axis, and further identify endocannabinoid signaling as a critical regulator of the stress response.
A rather complex and pleiotropic endogenous signalling system was discovered in the late 1990s, starting from studies on the mechanism of action of Delta(9)-tetrahydrocannabinol, the major psychoactive principle of the hemp plant Cannabis sativa. This system includes: (1) at least two G-protein-coupled receptors, known as the cannabinoid CB(1) and CB(2) receptors; (2) the endogenous agonists at these receptors, known as endocannabinoids, of which anandamide and 2-arachidonoylglycerol are the best known; and (3) proteins and enzymes for the regulation of endocannabinoid levels and action at receptors. The number of the members of this endocannabinoid signalling system seems to be ever increasing as new non-CB(1) non-CB(2) receptors for endocannabinoids, endocannabinoid-related molecules with little activity at CB(1) and CB(2) receptors, and new enzymes for endocannabinoid biosynthesis and degradation are being identified every year. The complexity of the endocannabinoid system and of its physiological and pathological function is outlined in this introductory chapter, for a better understanding of the subsequent chapters in this special issue.
Extensive documentation exists showing that exercise induces analgesia and sedation. Despite decades of research attempting to explicate a neurochemical basis for these phenomena, the mechanism underlying these changes is unknown. Using trained male college students running on a treadmill or cycling on a stationary bike for 50 min at 70-80% of maximum heart rate, we report here the first evidence that exercise of moderate intensity activates the endocannabinoid system, suggesting a new mechanism for exercise-induced analgesia and possibly other physiological and psychological adaptations to exercise.
The endocannabinoid anandamide is an emerging potential signalling molecule in the cardiovascular system. Anandamide causes vasodilatation, bradycardia and hypotension in animals and has been implicated in the pathophysiology of endotoxic, haemorrhagic and cardiogenic shock, but its vascular effects have not been studied in man.
Human forearm blood flow and skin microcirculatory flow were recorded using venous occlusion plethysmography and laser-Doppler perfusion imaging (LDPI), respectively. Each test drug was infused into the brachial artery or applied topically on the skin followed by a standardized pin-prick to disrupt the epidermal barrier.
Anandamide failed to affect forearm blood flow when administered intra-arterially at infusion rates of 0.3–300 nmol min−1. The highest infusion rate led to an anandamide concentration of approximately 1 μM in venous blood as measured by mass spectrometry.
Dermal application of anandamide significantly increased skin microcirculatory flow and coapplication of the transient receptor potential vanilloid 1 (TRPV1) antagonist capsazepine inhibited this effect. The TRPV1 agonists capsaicin, olvanil and arvanil all induced concentration-dependent increases in skin blood flow and burning pain when administered dermally. Coapplication of capsazepine inhibited blood flow and pain responses to all three TRPV1 agonists.
This study shows that locally applied anandamide is a vasodilator in the human skin microcirculation. The results are consistent with this lipid being an activator of TRPV1 on primary sensory nerves, but do not support a role for anandamide as a circulating vasoactive hormone in the human forearm vascular bed.
British Journal of Pharmacology (2005) 146, 171–179. doi:10.1038/sj.bjp.0706313
Anandamide (N-arachidonylethanolamine) is an endogenous cannabinoid receptor ligand that has been implicated in various physiological and pathophysiological functions. In the present study, a liquid-liquid extraction-based reversed-phase HPLC method with fluorometric detection was validated and applied for the analysis of anandamide in human plasma. Following derivatization with the fluorogenic reagent 4-(N,N-dimethylaminosulfonyl)-7-(N-chloroformylmethyl-N-methyl-amino)-2,1,3-benzoxadiazole (DBD-COCl), the analyte was separated using an acetonitrile-water gradient at a flow rate of 0.8 mL/min, and spectrophotometric detection at 560 nm with an excitation wavelength of 450 nm. The retention times for anandamide and R+-methanandamide (internal standard) were 27.1 and 30.7 min, respectively. The validated quantification range was 1-15 ng/mL. The developed procedure was applied to determine anandamide levels in human plasma following a 24 h incubation of human whole blood at 37 degrees C in the presence or absence of phenylmethylsulfonyl fluoride, an inhibitor of the anandamide-degrading enzyme fatty acid amide hydrolase. Anandamide levels determined under both conditions were within the validated concentration range with anandamide levels being 2.3-fold higher in plasma from PMSF-treated blood.
The CB1 cannabinoid receptor has attracted much recent interest because of the observation that CB1 receptor antagonists have efficacy in treating metabolic syndrome and obesity. CB1 receptors also mediate most of the psychotropic effects of Delta9-tetrahydrocannabinol (Delta9THC), the principal psychoactive component of cannabis. In addition, they are one component of an interesting and widespread paracrine signaling system, the endocannabinoid system. The endocannabinoid system is comprised of cannabinoid receptors, endogenous cannabinoids, and the metabolic pathways responsible for their synthesis and degradation. The details of the endocannabinoid system have been most thoroughly studied in the brain. Here it has been shown to be intimately involved in several forms of neuronal plasticity. That is, activation of CB1 receptors by endocannabinoids produces either short- or long-term changes in the efficacy of synaptic transmission. The behavioral consequences of these changes are many, but some of the most striking and relevant to the current symposium are those associated with endogenous reward and consumptive behavior.
Endogenous ligands of cannabinoid receptors (endocannabinoids), in particular anandamide (arachidonylethanolamide), have been recognized as being of crucial importance in a variety of physiological functions. Plasma concentrations of anandamide have been measured in a number of investigations; however, discrepant data on "normal" anandamide plasma concentrations were reported. Since this might be caused by pre-analytical variables, we investigated the impact of different sample handling conditions on measured plasma anandamide concentrations.
Blood samples were taken from healthy volunteers in EDTA- or heparin-containing tubes; whole blood samples were kept at +4 degrees C, room temperature, or 37 degrees C, respectively, for up to 120 min before obtaining plasma by centrifugation. Plasma anandamide concentrations were measured by an isotope-dilution liquid chromatography tandem mass spectrometry (LC-MS/MS) method.
A marked time- and temperature-dependent increase in plasma anandamide concentrations ex vivo was observed in both EDTA- and heparin-containing tubes. Mean anandamide concentrations approximately doubled when EDTA samples were kept at 4 degrees C for 60 min before centrifugation [immediately centrifuged, 1.3 microg/L (SD 0.3 microg/L); 2.8 microg/L (SD 0.5 microg/L) after storage for 60 min; n=12). After storage of heparinized whole-blood samples for 120 min at 37 degrees C, a mean plasma anandamide concentration of 11.9 microg/L (SD 1.8 microg/L) was found. In cell-free plasma, no increase in anandamide concentrations was found.
Anandamide is released from blood cells ex vivo at a very high rate; therefore, strictly standardized pre-analytical protocols have to be applied for plasma anandamide determination.
2-Arachidonoylglycerol (2-AG) is a unique molecular species of monoacylglycerol isolated in 1995 from rat brain and canine gut as an endogenous ligand for the cannabinoid receptors. 2-AG is rapidly formed from arachidonic acid-containing phospholipids through increased phospholipid metabolism, such as enhanced inositol phospholipid turnover, in various tissues and cells upon stimulation. 2-AG binds to the cannabinoid receptors (CB1 and CB2) and exhibits a variety of cannabimimetic activities in vitro and in vivo. Notably, anandamide, another endogenous ligand for the cannabinoid receptors, often acts as a partial agonist at these cannabinoid receptors, whereas 2-AG acts as a full agonist in most cases. The results of structure-activity relationship studies suggested that 2-AG rather than anandamide is the true natural ligand for both the CB1 and the CB2 receptors. Evidence is gradually accumulating which shows that 2-AG plays physiologically essential roles in diverse biological systems. For example, several lines of evidence indicate that 2-AG plays an important role as a retrograde messenger molecule in the regulation of synaptic transmission. 2-AG has also been shown to be involved in the regulation of various types of inflammatory reactions and immune responses. In this review, we focused on 2-AG, and summarized information concerning its biosynthesis, metabolism, bioactions and physiological significance, including our latest experimental results.
The endocannabinoid 2-arachidonoyl glycerol (2-AG) undergoes spontaneous isomerization to biologically inactive 1-AG. This effect has not been adequately addressed in previous studies that reported 2-AG concentrations in biological samples.
Liquid chromatography tandem-mass spectrometry (LC-MS/MS) was used for 1-AG and 2-AG analyses.
Identical collision-induced disintegration spectra were found for 1-AG and 2-AG. For specific detection of both compounds, which share a common mass transition, baseline chromatographic separation is mandatory, even when applying MS/MS technology with its generally high detection specificity. When using standard chromatographic conditions with the very short run times typically used in LC-MS/MS methods, co-elution of 2-AG with 1-AG, which is present in human serum, causes false 2-AG results.
Our data highlight that the analytical specificity of MS/MS can be limited by interference from isobaric isomers with identical disintegration patterns. The specificity of this technology must be carefully evaluated for each individual application.
The endocannabinoid system consists of the endogenous cannabinoids (endocannabinoids), cannabinoid receptors and the enzymes that synthesise and degrade endocannabinoids. Many of the effects of cannabinoids and endocannabinoids are mediated by two G protein-coupled receptors (GPCRs), CB(1) and CB(2), although additional receptors may be involved. CB(1) receptors are present in very high levels in several brain regions and in lower amounts in a more widespread fashion. These receptors mediate many of the psychoactive effects of cannabinoids. CB(2) receptors have a more restricted distribution, being found in a number of immune cells and in a few neurones. Both CB(1) and CB(2) couple primarily to inhibitory G proteins and are subject to the same pharmacological influences as other GPCRs. Thus, partial agonism, functional selectivity and inverse agonism all play important roles in determining the cellular response to specific cannabinoid receptor ligands.
Endocannabinoids in neuroim-munology and stress G(i)-dependent localization of beta(2)-adrenergic receptor signaling to L-type Ca(2?) channels
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Determination of the endocan-nabinoid anandamide in human plasma by high-performance liquid chromatography Exercise activates the endocannabinoid system
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Involvement of the endocannabinoid system in the neurobehavioural effects of stress and glucocor-ticoids An endocannabinoid mechanism for stress-induced analgesia
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Germany e-mail: alexander.chouker@med.uni-muenchen.de R. Toth School of Ph.D. studies Semmelweis University, U ¨ llö ut 26, Budapest 1085, Hungary F. Demetz Notfallklinik Endocannabinoids in neuroim-munology and stress G(i)-dependent localization of beta
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M. Feuerecker Á D. Hauer Á R. Toth Á F. Demetz Á I. Kaufmann Á G. Schelling Á A. Choukèr (&) Department of Anaesthesiology, Klinikum Großhadern, University of Munich, Marchioninistrasse 15, 81377 Munich, Germany e-mail: alexander.chouker@med.uni-muenchen.de R. Toth School of Ph.D. studies Semmelweis University, U ¨ llö ut 26, Budapest 1085, Hungary F. Demetz Notfallklinik, Klinikum Ingolstadt, Levelingstraße 21, 85049 Ingolstadt, Germany J. Hö Department of Medicine, South Tyrolean Mountain Rescue, Bolzano, Italy M. Thiel Clinic of Anaesthesiology and Intensive Care, Klinikum Mannheim, University of Mannheim, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany References Carrier EJ, Patel S, Hillard CJ (2005) Endocannabinoids in neuroim-munology and stress. Curr Drug Targets CNS Neurol Disord 4:657–665 Chen-Izu Y, Xiao RP, Izu LT, Cheng H, Kuschel M, Spurgeon H, Lakatta EG (2000) G(i)-dependent localization of beta(2)-adrenergic receptor signaling to L-type Ca(2?) channels. Biophys J 79:2547–2556