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Systemic vitamin C treatment prevented development of nociceptive sensitization after tibia fracture and casting.
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Clinical evidence suggests vitamin C (Vit C) may protect against the development of complex regional pain syndrome (CRPS) after fracture and/or surgery. Tibia fracture followed by 4 weeks cast immobilization (fracture/cast) in rats results in nociceptive, vascular, and bone changes resembling clinical CRPS. In the present study, fracture/cast rats...
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... nociceptive and vascular effects of tibia fracture followed by cast immobilization (fracture/cast) were examined in fracture/cast rats treated with a 4-week course of Vit C, an antioxidant, started at the time of fracture (Fig. 1). Fracture/cast resulted in hindpaw cutaneous von Frey allodynia with mean von Frey withdrawal threshold 8.5 g lower on the fracture/cast side than the contralateral side (−8.5 ± 0.4 Δg vs control nonfracture rats −0.4 ± 0.3 Δg, P<0.001). Vit C treatment reversed hindpaw allodynia (−8.5 ± 0.4 Δg to −3.3 ± 1.3 Δg, P<0.001). Fracture/cast ...
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... side (−8.5 ± 0.4 Δg vs control nonfracture rats −0.4 ± 0.3 Δg, P<0.001). Vit C treatment reversed hindpaw allodynia (−8.5 ± 0.4 Δg to −3.3 ± 1.3 Δg, P<0.001). Fracture/cast also reduced ipsilateral hindlimb weight-bearing to 53 ± 1% of the average of total weight bearing in the hindlimbs (P<0.001 compared to control nonfracture rats, Fig. 1B). Vit C treatment improved post fracture weight-bearing from 53 ± 1% to 95 ± 1% (P<0.001), indicating 89% improvement. Fracture/cast also resulted in gastrocnemius muscle hyperalgesia, with the Randall-Selitto withdrawal threshold lower on ipsilateral side than the contralateral side (−410 ± 13 Δg, vs control nonfracture rats 18.6±11.1 ...
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... muscle hyperalgesia (−410 ± 13 Δg to −246 ± 12.5 Δg, P<0.001), indicating 38% improvement. Fracture/cast induced hindpaw warmth, as indicated by the greater difference in skin temperature between ipsilateral and contralateral sides in fracture/cast rats (4.6 ± 0.7 Δ ° C) than that in the nonfracture control rats (0.0 ± 0.1 Δ ° C, P<0.001, Fig. 1D), but Vit C treatment had no significant effect on hindpaw warmth. Fracture/cast also resulted in edema, as indicated by the greater difference in skin thickness between ipsilateral and contralateral sides in fracture/ cast rats (1.5 ± 0.4 Δmm) than that in the control rats (0.0 ± 0.1 Δmm, P<0.01, Fig. 1E), and Vit C treatment had no ...
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... control rats (0.0 ± 0.1 Δ ° C, P<0.001, Fig. 1D), but Vit C treatment had no significant effect on hindpaw warmth. Fracture/cast also resulted in edema, as indicated by the greater difference in skin thickness between ipsilateral and contralateral sides in fracture/ cast rats (1.5 ± 0.4 Δmm) than that in the control rats (0.0 ± 0.1 Δmm, P<0.01, Fig. 1E), and Vit C treatment had no significant effect on hindpaw ...
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WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: This study tested the hypothesis that ad lib running wheel exercise in a tibia fracture model of complex regional pain syndrome can reverse hindlimb nociceptive sensitization and inflammation in mice.
Methods:
Three weeks after tibia fracture, the cast wa...
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... The etiology and pathogenesis of CRPS may exhibit inter-individual heterogeneity and even intra-individual variability over time (44,49,50). The most common inciting events are surgery, nerve compression, fractures, tissue trauma, ischemia, and sprains (27, 51).4 Inflammation (52), oxidative stress (53), and neuronal mechanisms have been postulated as pivotal factors in the pathogenesis of CRPS (50,54). Current evidence suggests that the development of CRPS involves multiple mechanisms originating from a complex interplay between the immune system, the neural systems (including the peripheral nervous system (PNS), central nervous system (CNS), and autonomic nervous system), and genetic predisposition (55) (Figure 1). ...
Complex Regional Pain Syndrome (CRPS) is a chronic pain disorder characterized by a diverse array of symptoms, including pain that is disproportionate to the initial triggering event, accompanied by autonomic, sensory, motor, and sudomotor disturbances. The primary pathology of both types of CRPS (Type I, also known as reflex sympathetic dystrophy, RSD; Type II, also known as causalgia) is featured by allodynia, edema, changes in skin color and temperature, and dystrophy, predominantly affecting extremities. Recent studies started to unravel the complex pathogenic mechanisms of CRPS, particularly from an autoimmune and neuroimmune interaction perspective. CRPS is now recognized as a systemic disease that stems from a complex interplay of inflammatory, immunologic, neurogenic, genetic, and psychologic factors. The relative contributions of these factors may vary among patients and even within a single patient over time. Key mechanisms underlying clinical manifestations include peripheral and central sensitization, sympathetic dysregulation, and alterations in somatosensory processing. Enhanced understanding of the mechanisms of CRPS is crucial for the development of effective therapeutic interventions. While our mechanistic understanding of CRPS remains incomplete, this article updates recent research advancements and sheds light on the etiology, pathogenesis, and molecular underpinnings of CRPS.
... In light of the aforementioned considerations, a potential strategy to disrupt this cycle of oxidative stress and inflammation lies in the systemic administration of antioxidants. Insights from animal studies suggest that systemic antioxidants, such as vitamin C, have the capacity to mitigate oxidative stress triggered by injuries (96). Beyond their role in pain reduction, antioxidants may also serve as a valuable tool for enhancing and expediting the scale of the inflammatory response. ...
... Sistemik tedavi olarak antioksidanların, C vitamini gibi antioksidanların sistemik uygulanmasının yaralanma kaynaklı oksidatif stresi azalttığına dair kanıtlar vardır (Guo et al., 2018). Ayrıca ağrıyı azaltmak dışında antioksidanlar da inflamatuar yanıtın düzelmesini/ çözülmesini hızlandırmak için kullanılabilir. ...
... Hyperbaric oxygen therapy was assessed in a medium sized randomized control trial (RCT) and produced a significant decrease in pain and edema versus "normal air" (level 2) [115]. While intriguing, these findings of increased oxygenation having clinical benefits seem somewhat contrary to other work suggesting that CRPS may be adversely influenced by elevated oxidative stress [116][117][118]. These findings require replication, and cost-benefit considerations of this therapy will also be important to consider, given the expense of the equipment required. ...
There have been some modest recent advancements in the research of Complex Regional Pain Syndrome, yet the amount and quality of the work in this complicated multifactorial disease remains low (with some notable exceptions; e.g., the recent work on the dorsal root ganglion stimulation). The semi-systematic (though in some cases narrative) approach to review is necessary so that we might treat our patients while waiting for "better research." This semi-systematic review was conducted by experts in the field, (deliberately) some of whom are promising young researchers supplemented by the experience of "elder statesman" researchers, who all mention the system they have used to examine the literature. What we found is generally low- to medium-quality research with small numbers of subjects; however, there are some recent exceptions to this. The primary reason for this paucity of research is the fact that this is a rare disease, and it is very difficult to acquire a sufficient sample size for statistical significance using traditional statistical approaches. Several larger trials have failed, probably due to using the broad general diagnostic criteria (the "Budapest" criteria) in a multifactorial/multi-mechanism disease. Responsive subsets can often be identified in these larger trials, but not sufficient to achieve statistically significant results in the general diagnostic grouping. This being the case the authors have necessarily included data from less compelling protocols, including trials such as case series and even in some instances case reports/empirical information. In the humanitarian spirit of treating our often desperate patients with this rare syndrome, without great evidence, we must take what data we can find (as in this work) and tailor a treatment regime for each patient.
... Apart from its anti-inflammatory properties, artemisinin and its derivatives can activate the antioxidant system to exert potent neuroprotective effects on hydrogen peroxide (H 2 O 2 )induced retinal neuronal dysfunction, sodium nitroprussideinduced cortical neurotoxicity, and neurodegenerative disease (Zheng et al., 2016;Yan et al., 2017;Li et al., 2019). Oxidative insult-related spinal nociception sensitization has been identified to be a cardinal step for the generation of fracture-induced pain (Guo et al., 2018;Guo et al., 2021). Accordingly, further investigations are warranted to study whether oxidative molecular signaling is involved in artesunate analgesia for fracture intervention. ...
Chronic pain after bone fracture and orthopedic surgery is often refractory to most analgesics currently in use, thus emphasizing the urgent need for improved therapeutic medications. Chemokine-dependent neuroinflammation is critical for excitatory synaptic plasticity and central nociception sensitization. Recent studies have focused on the inhibition of inflammatory responses by artesunate, the first anti-malaria drug extracted from artemisinin. The present study investigated the analgesic effects and potential targets of artesunate in a mouse model of chronic pain induced by tibial fracture and orthopedic surgery. Three injections of artesunate were intrathecally administered on a daily basis from days 4 to 6 after fracture. We reported that repetitive exposure to artesunate (10 and 100 μg but not 1 μg) dose-dependently prevented fracture-induced mechanical and cold allodynia. Moreover, single intrathecal injection of artesunate (100 μg) alleviated the established chronic pain on day 14 after fracture surgery. Intraperitoneal artesunate (10 and 50 mg kg ⁻¹ ) therapy was effective against chronic fracture pain. Intriguingly, artesunate inhibited the upregulation of spinal chemokine CCL21, triggering receptor expressed on myeloid cells 2 (TREM2) and DNAX-activating protein of 12 kDa (DAP12) expressions and microglia activation in fracture mice. Furthermore, spinal CCL21 neutralization attenuated the severity of fracture-associated post-surgical pain. Exogenous CCL21-induced acute inflammatory pain was impaired by artesunate therapy. Additionally, the pharmacological blockage of TREM2 reduced recombinant CCL21-elicited behavioral hypernociception. The present findings demonstrate that artesunate therapy reduces the initiation and maintenance of fracture-associated chronic postoperative pain by inhibiting CCL21-dependent TREM2/DAP12 inflammatory signaling and microglia activation, thus suggesting that artesunate could emerge as a therapeutic strategy for fracture pain management.
... Administration of antioxidants reduces lung SP level in rats and further attenuating (MCT)-induced pulmonary hypertension [44]. oxidative stress has been suggested as a possible mechanism involved in upregulation of SP signaling after fracture, as using anti-oxidant vitamin C (Vit C) to limit oxidative stress in a rat model of complex regional pain syndrome (CRPS) results in inhibition of the post-fracture up-regulation of sciatic SP content [45,46]. The potential mechanisms used by ROS to induce SP release are based on the following findings. ...
Oxidative stress which refers to redox imbalance with increased generation of reactive oxygen species (ROS) has been associated with the pathophysiology of diverse disease conditions. Recently, a close, yet not fully understood, relation between oxidative stress and neuropeptides, in particular, substance P (SP), has been reported in certain conditions. SP has been shown to affect the cellular redox environment through activation of neurokinin-1receptor (NK1R). It seems that SP/NK1R system and oxidative stress can act either synergistically or antagonistically in a context-dependent manner, thereby, influencing the pathology of various clinical disorders either destructively or protectively. Importantly, the interactions between oxidative stress and SP/NK1R system can be pharmacologically targeted. Therefore, a better understanding of the redox modulatory properties of SP/NK1R signaling will pave the way for identifying new therapeutic possibilities for attenuating oxidative stress-mediated damage. Towards this end, we performed a comprehensive search through PubMed/Medline and Scopus databases and discussed all related existing literature regarding the interplay between oxidative stress and SP/NK1R system as well as their implication in various clinical disorders, to provide a clear view and hence better management of oxidative damage.
... Oxidative stress is a biological phenomenon that occurs when there is an imbalance between free radical compounds, such as reactive oxygen species (ROS) or reactive nitrogen species (RNS), and antioxidant defense systems in the body [123][124][125]. This imbalance leads to the destruction of cells and molecules, impacting the whole system [126]. ...
Investigating the disproportionate rates of chronic pain and their related comorbidities between Black and non-Hispanic White (White) individuals is a growing area of interest, both in the healthcare community and in general society. Researchers have identified racial differences in chronic pain prevalence and severity, but still very little is known about the mechanisms underlying them. Current explanations for these differences have primarily focused on socioeconomic status and unequal healthcare between races as causal factors. Whereas these factors are informative, a racial gap still exists between Black and White individuals when these factors are controlled for. One potential cause of this racial gap in chronic pain is the differences in nutrition and dietary intake between groups. Certain foods play a key role in the inflammatory and oxidative stress pathways in the human body and could potentially influence the severity of the pain experience. Here, we review the previous literature on the surrounding topics and propose a potential mechanism to explain racial differences in the chronic pain population, based on established racial differences in diet and oxidative stress.
... However, the model is not directly comparable to non-pathological fracture-induced pain due to the immobilisation of the limb, which induces physiological changes such as oxidative stress, vascular and inflammatory alterations that contribute to the pain phenotype observed which are not directly attributable to the fracture itself. 37 Most studies of fracture pain used mice, but the rat model of closed femur fracture model has the advantage of a more accessible central nervous system for electrophysiology studies of pain compared to the mouse. 38 ...
Progress in bone fracture repair research has been made possible due to the development of reproducible models of fracture in rodents with more clinically relevant fracture fixation, where there is considerably better assessment of the factors that affect fracture healing and/or novel therapeutics. However, chronic or persistent pain is one of the worst, longest-lasting and most difficult symptoms to manage after fracture repair, and an ongoing challenge remains for animal welfare as limited information exists regarding pain scoring and management in these rodent fracture models. This failure of adequate pre-clinical pain assessment following osteotomy in the rodent population may not only subject the animal to severe pain states but may also affect the outcome of the bone healing study. Animal models to study pain were also mainly developed in rodents, and there is increasing validation of fracture and pain models to quantitatively evaluate fracture pain and to study the factors that generate and maintain fracture pain and develop new therapies for treating fracture pain. This review aims to discuss the different animal models for fracture pain research and characterize what can be learned from using animal models of fracture regarding behavioral pain states and new molecular targets for future management of these behaviors.
... The present study shows that LY2456302 reinstated hyperalgesia in male mice when administered not just 6 months, but even 13 months after incision. This extends the known duration of LS and its opposing inhibition to over a year, making LS among the longest-lasting rodent models of chronic pain, rivaling the time course of the tibia fracture model of complex regional pain syndrome (Tajerian et al., 2015;Wang et al., 2016;Guo et al., 2018) and the spared nerve injury model of neuropathic pain (Decosterd and Woolf, 2000;Intondi et al., 2010). ...
Latent pain sensitization (LS) engages pronociceptive signaling pathways in the dorsal horn that include N-methyl-D-aspartate receptor (NMDAR) → adenylyl cyclase-1 (AC1) → protein kinase A (PKA) and Exchange factor directly activated by cAMP (Epac). To determine whether these pathways operate similarly between males and females or are under the inhibitory control of spinal kappa opioid receptors (KOR), we allowed hyperalgesia to resolve after plantar incision and then blocked KOR with intrathecal administration of LY2456302. LY2456302 reinstated hyperalgesia and facilitated touch-evoked immunoreactivity of phosphorylated extracellular signal-regulated kinase (pERK) in neurons (NeuN) but neither astrocytes (GFAP) nor microglial (Iba1). LY2456302 reinstated hyperalgesia even when administered 13 months later, indicating that chronic postoperative pain vulnerability persists for over a year in a latent state of remission. In both sexes, intrathecal MK-801 (an NMDAR competitive antagonist) prevented LY2456302-evoked reinstatement of hyperalgesia, as did AC1 gene deletion or the AC1 inhibitor NB001. NB001 also prevented stimulus-evoked pERK. In both sexes, the Epac inhibitor ESI-09 prevented reinstatement, while the Epac activator 8-CPT reinstated hyperalgesia. By contrast, only in male mice did the PKA inhibitor H89 prevent reinstatement, while the PKA activator 6-bnz-cAMP itself evoked reinstatement at all doses tested (3-30 nmol, i.t.). In neither sex did incision change gene expression of KOR, GluN1, PKA or Epac1 in dorsal horn. We conclude that sustained KOR signaling inhibits spinal PKA-dependent mechanisms that drive postoperative LS in a sex-dependent manner. Our findings support the development of AC1, PKA, and Epac inhibitors towards a new pharmacotherapy for chronic postoperative pain.
... It would seem that oxidative stress plays critical role in several mechanisms involved in nociception induction and central nervous system sensitization [5]. Indeed, a recent report suggested that oxidative stress contributes to the increase of expression of nociception-related inflammatory mediators [6]. However, the interaction between pain and oxidative stress mechanisms remains controversial and not straightforward [7]. ...
Aims: Adenia lobata (Jacq.) Engl. (Passifloraceae) is widely used in Ivorian traditional pharmacopeia to heal various chronic diseases, relieve headache and pain of gingiva inflammation, and facilitate labor. Here, we investigated the effects of hydroethanolic extract Adenia lobata (HEAL) on nociceptive pain and subsequent anxiety-like behavior. Materials and Methods: We used several experimental pain tests as the writhing, formalin and hot plate to evaluate both antinociceptive and anti-inflammatory actions of the extract. Anxiety related to nociception was tested with open field and elevated plus maze tests. Then, mice were sacrificed for assessing some oxidative stress markers. Results: The extract of 30 mg/kg, p.o. reduced in the similar manner as reference peripheral drug salcylicacetic acid (ASA, 200 mg/kg, i.p.) the number of writhings induced by acid acetic. In both neurogenic and inflammatory phases of formalin test, the extract demonstrated an effective antinociceptive activity than ASA, but comparable to central analgesic tramadol (50 mg/kg, i.p). However, Adenia lobata reduced lesser thermal-induced pain than tramadol in hot plate test, but significantly compared to ASA. Furthermore, HEAL altered anxiety-like behavior in each case of the pain condition studied. Also, the extract showed the highest antioxidant activity by reduction oxide nitric (NO) and malondialdehyde (MDA), and increase non protein thiol (NP-SH) levels. Conclusion: In conclusion, HEAL possesses antinociceptive and anti-inflammatory actions on peripheral and central mechanisms of pain. The phytochemicals components of the extract as alkaloids and flavonoids suggest to interact with the opioid system and combat the oxidative stress, respectively. Our findings provide scientific basis for the use of Adenia lobata in traditional medicine against pain and related diseases.
