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Schematic illustration of the role of spinal microglia in mediating visceral hyperalgesia in a rat model of trinitrobenzene sulfonic acid (TNBS)-intraductal injection to induce chronic pancreatitis (CP). Minocycline can inhibit and prevent the microglia activation and the associated visceral hyperalgesia in TNBSinduced CP rat model.
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Chronic visceral pain is the predominant symptom of functional gastrointestinal disorders and chronic pancreatitis. Such pain can impair the patients' quality of life, and can also serve as one of the principal reasons for these patients to seek medical help. Nevertheless, the underlying mechanisms of chronic visceral pain have remained unclear, an...
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Context 1
... thoracic spinal cord in CP rats (Fig. 1). P-p38 levels were also increased in CP rats and colocalized with OX42-positive cells, but in neither NeuN-positive (neuron) nor GFAP-positive (astrocyte) cells. Intrathecal injection of minocycline would not only reverse, but also prevent the increase of nocifensive behaviors and P-p38 levels in CP rats (Fig. 2). FKN would induce visceral hyperalgesia in non-CP rats, which was also blocked by minocycline. We also found that the spinal Ik-B level was significantly decreased after TNBS-induced pancreatitis; the Ik-B level reversed to normal after minocy- cline treatment (unpublished data). This finding suggests the importance of NF-kB signaling ...
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Angina pectoris is cardiac pain that is a common clinical symptom often resulting from myocardial ischemia. Spinal cord stimulation (SCS) is effective in treating refractory angina pectoris, but its underlying mechanisms have not been fully elucidated. The spinal dorsal horn is the first region of the central nervous system that receives nociceptiv...
Citations
... Microglia are considered the immune-like macrophages of the CNS and make up 5-12% of the total CNS glial population (63,110). As the custodians of the CNS, microglia are normally in a quiescent status and are activated upon infection, injury, or other disease states (110). ...
... Microglia are considered the immune-like macrophages of the CNS and make up 5-12% of the total CNS glial population (63,110). As the custodians of the CNS, microglia are normally in a quiescent status and are activated upon infection, injury, or other disease states (110). Once activated, they congregate in the dorsal horn of the spinal cord, where they can contribute to pain states by releasing proinflammatory cytokines, chemokines, and extracellular proteases (154). ...
The gut-brain axis is a coordinated communication system that not only maintains homeostasis, but significantly influences higher cognitive functions and emotions as well as neurological and behavioral disorders. Among the large populations of sensory and motor neurons that innervate the gut, insights into the function of primary afferent nociceptors whose cell bodies reside in the dorsal root ganglia and nodose ganglia, have revealed their multiple crosstalk with several cell types within the gut wall, including epithelial, vascular and immune cells. These bi-directional communications have immunoregulatory functions, control host response to pathogen, and modulate sensation associated with gastrointestinal disorders, through activation of immune cells and glia in the peripheral and central nervous system, respectively. Here we will review the cellular and neurochemical basis of these interactions at the periphery, in dorsal root ganglia and in the spinal cord. We will discuss the research gaps that should be addressed to get a better understanding of the multifunctional role of sensory neurons in maintaining gut homeostasis and regulating visceral sensitivity.
... Notably, single administration of minocycline could temporarily suppress pain allergies in present study (Fig. 8), but did not reverse persistent pain, which was in agreement with Ledeboer' study (Ledeboer et al., 2005). Though, Minocycline maybe reverse hyperalgesia in chronic visceral pain rats (Lu, 2014), and continuous administration of minocycline increases anti-nociceptive factors (IL-1α, IL-2, IL-10) in diabetic rat (Zychowska et al., 2013), and anti-depressive-like effect in painful diabetic neuropathy. Minocycline could significantly decrease p38 MAPK in spinal dorsal horn microglia, but the exact upstream target remains unknown. ...
Recent studies have implicated the activation of p38 mitogen-activated protein kinase (MAPK) and glial cells contribute to hyperalgesia following nerve injury or nerve compression. In our work, we investigated the underlying mechanisms of autologous nucleus pulposus (NP)-induced mechanical hyperalgesia in a modified rat model of lumbar disk herniation (LDH). Firstly, our results showed that 50% mechanical withdrawal threshold (50% MWT) decreased on postoperative day (POD) 1 and significantly minimally reduced on POD 7and lasted for day 28 after surgery(P<0.05). Secondly, phosphorylation of p38MAPK (p-p38MAPK) and glial cells were monitored on POD 1、3、7、14 and 28 using immunofluorescence staining. P38MAPK activation, observed in the spinal cord, began to increase on POD 1, peaked on POD 3, and significantly decreased on POD 14 and POD 28(P<0.05). Microglia activation was initiated at day 1, maximal at day 3, and maintained until day 14 after surgery(P<0.05). Astrocytic activation was found in 7 to 14 days after modelling(P<0.05). Then, double immunostaining method was applied to observe the co-expression of p-p38MAPK and glial cells, and it showed that p-p38MAPK was mainly expressed in activated microglia, rarely in neurons, and none in astrocytes. Lastly, we discovered that both SB203580 (50ug, p38MAPK inhibitor) and minocycline (0.5mg, microglial inhibitor) would inhibit the p-p38MAPK protein expression tested by western blot analysis and reduce mechanical hyperalgesia. In conclusion, current study suggest that activation or phosphorylation of p38MAPK in spinal microglia contributes to autologous NP-induced mechanical hyperalgesia in our animal model.
... The past few years mark a shift in traditional allopathic approach to combating pain. Instead of utilizing just pharmacotherapy that consists of well-known traditional analgesics and anti-inflammatories as well as adjunctive medication such as antidepressants and anti-epileptics, immunomodulation seems to be entering as the next step in pain-research and clinical practice also [185][186][187]. By understanding the intercellular and intracellular signalling in chronic pain, the traditional paradigm of considering just the neuronal component is expanding heavily to include the area of glia [188,189]. ...
Background and purpose (aims):
Psychoneuroimmunology is both a theoretical and practical field of medicine in which human biology and psychology are considered an interconnected unity. Through such a framework it is possible to elucidate complex syndromes in gastrointestinal related pain, particularly chronic non-malignant. The aim is to provide insight into pathophysiological mechanisms and suggest treatment modalities according to a comprehensive paradigm. The article also presents novel findings that may guide clinicians to recognize new targets or scientists to find new research topics.
Methods:
A literature search of 'PubMed' and 'Google Scholar' databases was performed. Search terms included: 'Visceral pain', 'Psychoneuroimmunology', 'Psychoneuroimmunology and pain', 'Pain in GI system', 'GI related pain', 'Pain and microbiota', 'Enteric nervous system', 'Enteric nervous system and inflammation', 'CNS and pain', 'Inflammation and pain in GI tract', 'Neurogastroenterology', 'Neuroendocrinology', 'Immune system in GI pain'. After searching and reading sources deemed recent and relevant, a narrative review was written with a tendency to discriminate the peripheral, intermediate, and central pathophysiological mechanisms or treatment targets.
Results:
Recent evidence point out the importance of considering the brain-gut axis as the main connector of the central and peripheral phenomena encountered in patients suffering from chronic non-malignant gastrointestinal related pain. This axis is also a prime clinical target with multiple components to be addressed in order for therapy to be more effective. Patients suffering from inflammatory bowel disease or functional gastrointestinal disorders represent groups that could benefit most from the proposed approach.
Conclusions (based on our findings):
Rather than proceeding with established allopathic single-target central or peripheral treatments, by non-invasively modulating the brain-gut axis components such as the psychological and neuroendocrinological status, microbiota, enteric nervous system, or immune cells (e.g. glial or mast cells), a favourable clinical outcome in various chronic gastrointestinal related pain syndromes may be achieved. Clinical tools are readily available in forms of psychotherapy, prebiotics, probiotics, nutritional advice, and off-label drugs. An example of the latter is low-dose naltrexone, a compound which opens the perspective of targeting glial cells to reduce neuroinflammation and ultimately pain.
Implications (our opinion on what our findings mean):
Current findings from basic science provide sound mechanistic evidence and once entering clinical practice should yield more effective outcomes for patients. In addition to well-established pharmacotherapy comprised notably of anti-inflammatories, antibiotics, and proton-pump inhibitors, valid treatment strategies may contain other options. These disease modulating add-ons include probiotics, prebiotics, food supplements with anti-inflammatory properties, various forms of psychotherapy, and low-dose naltrexone as a glial modulator that attenuates neuroinflammation. Clearly, a broader and still under exploited set of evidence-based tools is available for clinical use.
... Consequently, the involvement of neuroimmune signaling in persistent pain attributed to visceral inflammation has gained interest in the past few years. 139 ...
In the central nervous system, bidirectional signaling between glial cells and neurons ('neuroimmune communication') facilitates the development of persistent pain. Spinal glia can contribute to heightened pain states by a prolonged release of neurokine signals that sensitize adjacent centrally projecting neurons. Although many persistent pain conditions are disproportionately common in females, whether specific neuroimmune mechanisms lead to this increased susceptibility remains unclear. This review summarizes the major known contributions of glia and neuroimmune interactions in pain, which has been determined principally in male rodents and in the context of somatic pain conditions. It is then postulated that studying neuroimmune interactions involved in pain attributed to visceral diseases common to females may offer a more suitable avenue for investigating unique mechanisms involved in female pain. Further, we discuss the potential for primed spinal glia and subsequent neurogenic inflammation as a contributing factor in the development of peripheral inflammation, therefore, representing a predisposing factor for females in developing a high percentage of such persistent pain conditions.
... En effet, p38 est largement étudié dans les pathologies viscérales et dans la douleur périphérique (Noguchi, Kondo et al. 2012;Dai, Zong et al. 2014). L'action des AL sur la voie Scr et les TLR-4 est surtout connue dans des modèles infectieux mais n'a jamais été étudiée dans un modèle d'inflammation chirurgicale (Piegeler, Dull et al. 2014 (Ji, Kawasaki et al. 2006;Liu, Lu et al. 2012;Lu 2014). ...
La douleur abdominale post chirurgicale reste une douleur difficile à gérer. Cette douleur présente 2 composantes : (1) une composante pariétale liée à l’agression des muscles de la paroi abdominale et du péritoine pariétal et (2) une composante viscérale liée à l’agression du péritoine viscérale et des viscères. La douleur pariétale est bien systématisée, elle correspond à des métamères bien identifiés. Par contre la douleur viscérale est souvent mal localisée, irradiée ou transférée à un site cutané. Les AL administrés par l’intermédiaire d’un cathéter d’infiltration pariétal, d’un bloc de la paroi abdominale ou par voie systémique montrent une efficacité clinique dans l’analgésie post opératoire d’une chirurgie abdominale. Cependant le mécanisme d’action des AL en fonction de leurs voies d’administration n’est pas bien élucidé. Le but de nos études est d’explorer l’effet des AL sur les deux composantes de la douleur abdominale dans un modèle animal en fonction de leur voie d’administration. Nous avons réalisé 3 études expérimentales :1-Dans l’étude 1 nous avons comparé l’effet de la ropivacaïne administrée par voie systémique ou par un cathéter pré péritonéal sur la douleur pariétale et viscérale dans un modèle de laparotomie chirurgicale chez le rat.. 2-Dans l’étude 2 nous avons validé un bloc de la paroi abdominale chez le rat.. 3-Dans l’étude 3 nous avons comparé l’effet de la bupivacaïne par voie systémique à l’effet obtenu par l’administration de la bupivacaïne par un bloc de la paroi abdominale. Nous avons également comparé l’effet des Al par voie systémique à une vagotomie chimique préventive. L’ensemble de ces travaux montrent que lors d’une laparotomie, les AL sont efficaces dans le traitement de la nociception aussi bien par voie systémique que par voie locorégionale. Nous avons démontré qu’un bloc de la paroi abdominale, ainsi qu’une infiltration pré péritonéale diminuaient la transmission de la nociception viscérale vers le SNC par action directe sur les terminaisons nerveuses pariétales. De plus, lors d’une laparotomie, l’administration systémique d’AL montre une efficacité dans l’inhibition de la transmission de la nociception viscérale vers le SNC associée à un effet anti inflammatoire local et systémique supérieure à celui d’une administration locorégionale.
... However, recent studies have demonstrated that the nociceptive processing in the central nervous system (CNS) contributes to CP-induced pain (7)(8)(9). Specifically, activation of the spinal cord microglias and astrocytes was detected in CP-induced pain, similar to that seen in neuropathic pain induced by peripheral nerve damages (8,10). Spinal astrocytes, once activated in neuropathic pain, express the protein marker glial fibrillary acidic protein (GFAP) and release inflammatory cytokines, including interleukin beta (IL-1β) and tumor necrosis factor alpha (TNF-α), promoting inflammation and pain (11,12). ...
Chronic pancreatitis (CP) is a long-standing inflammation of the exocrine pancreas, which typically results in severe and constant abdominal pain. Previous studies on the mechanisms underlying CP-induced pain have primarily focused on the peripheral nociceptive system. A role for a central mechanism in the mediation or modulation of abdominal pain is largely unknown. Tanshinone IIA (TSN IIA), an active component of the traditional Chinese medicine Danshen, exhibits anti-inflammatory properties via downregulation of the expression of high-mobility group protein B1 (HMGB1), a late proinflammatory cytokine. HMGB1 binds and activates toll-like receptor 4 (TLR4) to induce spinal astrocyte activation and proinflammatory cytokine release in neuropathic pain.
In this study, we investigated the effect of TSN IIA on pain responses in rats with trinitrobenzene sulfonic acid (TNBS)-induced CP. The roles of central mechanisms in the mediation or modulation of CP were also investigated.
A randomized, double-blind, placebo-controlled animal trial.
CP was induced in rats by intrapancreatic infusion of trinitrobenzene sulfonic acid (TNBS). Pancreatic histopathological changes were characterized with semi-quantitative scores. The abdomen nociceptive behaviors were assessed with von Frey filaments. The effects of intraperitoneally administered TSN IIA on CP-induced mechanical allodynia were tested. The spinal protein expression of HMGB1 was determined by western blot. The spinal mRNA and protein expression of proinflammatory cytokines IL-1β, TNF-α, and IL-6 were determined by RT-PCR and western blot, respectively. The spinal expression of the HMGB1 receptor TRL4 and the astrocyte activation marker glial fibrillary acidic protein (GFAP) were determined by western blot or immunohistological staining after intraperitoneal injection of TSN IIA or intrathecal administration of a neutralizing anti-HMGB1 antibody.
TNBS infusion resulted in pancreatic histopathological changes of chronic pancreatitis and mechanical allodynia in rats. TSN IIA significantly attenuated TNBS-induced mechanical allodynia in a dose-dependent manner. TNBS significantly increased the spinal expression of HMGB1 and proinflammatory cytokines IL-1β, TNF-α, and IL-6. These TNBS-induced changes were significantly inhibited by TSN IIA in a dose-dependent manner. Furthermore, TSN IIA, but not the neutralizing anti-HMGB1 antibody, significantly inhibited TNBS-induced spinal TLR4 and GFAP expression.
In addition to TLR4, HMGB1 can also bind to toll-like receptor-2 (TLR2) and the receptor for advanced glycation end products (RAGE). Additional studies are warranted to ascertain whether HMGB1 contributes to CP-induced pain through activation of these receptors.
Our results suggest that spinal HMGB1 contributes to the development of CP-induced pain and can potentially be a therapeutic target. TSN IIA attenuates CP-induced pain via downregulation of spinal HMGB1 and TRL4 expression. Therefore, TSN IIA may be a potential anti-nociceptive drug for the treatment of CP-induced pain.
Chronic pancreatitis, HMGB1, proinflammatory cytokine, Tanshinone IIA, spinal cord, astrocyte, TLR4.
... Microglia represent the first line of defense for the CNS, acting as a sensor for pathological events (268). The process of central sensitization and the subsequent changes in synaptic plasticity has long been thought to play a major role in nociceptive processes both in the context of chronic pain as well as acute, in both somatic and visceral modalities (269,270). In the last decade, the role of microglia, both spinal and supra-spinal, has become an area of interest in the context of nociception (271)(272)(273). ...
... The role of spinal microglia in visceral pain has only recently been addressed and reviewed nicely by Lu (269). Saab and colleagues were first to report increased activated microglia in a rat model of chronic visceral hyperalgesia, namely the neonatal colon irritation model (280). ...
... Saab and colleagues were first to report increased activated microglia in a rat model of chronic visceral hyperalgesia, namely the neonatal colon irritation model (280). Moreover, minocycline, a secondgeneration tetracycline compound known to interrupt microglia activation and its associated pro-inflammatory response, reversed the visceral hypersensitivity in adulthood (269,280). ...
Visceral pain is a global term used to describe pain originating from the internal organs, which is distinct from somatic pain. It is a hallmark of functional gastrointestinal disorders such as irritable-bowel syndrome (IBS). Currently, the treatment strategies targeting visceral pain are unsatisfactory, with development of novel therapeutics hindered by a lack of detailed knowledge of the underlying mechanisms. Stress has long been implicated in the pathophysiology of visceral pain in both preclinical and clinical studies. Here, we discuss the complex etiology of visceral pain reviewing our current understanding in the context of the role of stress, gender, gut microbiota alterations, and immune functioning. Furthermore, we review the role of glutamate, GABA, and epigenetic mechanisms as possible therapeutic strategies for the treatment of visceral pain for which there is an unmet medical need. Moreover, we discuss the most widely described rodent models used to model visceral pain in the preclinical setting. The theory behind, and application of, animal models is key for both the understanding of underlying mechanisms and design of future therapeutic interventions. Taken together, it is apparent that stress-induced visceral pain and its psychiatric comorbidities, as typified by IBS, has a multifaceted etiology. Moreover, treatment strategies still lag far behind when compared to other pain modalities. The development of novel, effective, and specific therapeutics for the treatment of visceral pain has never been more pertinent.
... The data illuminates that new analgesia mechanisms possibly exist in some forthcoming anesthetic to which structural modification can be manipulated to improve targeting. Moreover, antibiotic minocycline as a microglia inhibitor can reverse hyperalgesia which is also associated with elevated phosphorylation of p38 in rat models of chronic visceralpain, whereas fractalkine as a microglia activator reproduced the visceral nociception in naïve rats [120]. In CCI models, microinjection of minocycline (10mg/ml,0.2μl in the ventral posterolateral (VPL) contralateral to CCI reversed thermal hyperalgesia by abrogating the increased expression of OX-42 co-localized with phosphorylated p38MAPK [121]. ...
p38 mitogen-activated protein kinases (p38 MAPK, p38) consist of 4 subunits: p38α, p38β, p38γ and p38δ. They play a well-recognized role in regulating intracellular signaling transduction in mammalian cells. p38 MAPK induces a variety of intracellular responses associated with neuropathic pain and other chronic pain. Thus, specific targeting p38 MAPK molecule and its signaling pathway represent potential therapeutic strategies for pain management. Based on the understanding of the crystal structure, biological functions and its signaling pathway of p38 MAPK, chemically synthesized p38 MAPK inhibitors have become available. Natural products and biological components may also serve as potential p38 MAPK inhibitors. To this end, we will evaluate their potential for chronic pain management.
... The data illuminates that new analgesia mechanisms possibly exist in some forthcoming anesthetic to which structural modification can be manipulated to improve targeting. Moreover, antibiotic minocycline as a microglia inhibitor can reverse hyperalgesia which is also associated with elevated phosphorylation of p38 in rat models of chronic visceralpain, whereas fractalkine as a microglia activator reproduced the visceral nociception in naïve rats [120]. In CCI models, microinjection of minocycline (10mg/ml,0.2μl in the ventral posterolateral (VPL) contralateral to CCI reversed thermal hyperalgesia by abrogating the increased expression of OX-42 co-localized with phosphorylated p38MAPK [121]. ...
p38 mitogen-activated protein kinases (p38 MAPK, p38) consist of 4 subunits: p38α#945;, p38β#946;, p38γ#947; and p38α#948;. They play a well-recognized role in regulating intracellular signaling transduction in mammalian cells. p38 MAPK induces a variety of intracellular responses associated with neuropathic pain and other chronic pain. Thus, specific targeting p38 MAPK molecule and its signaling pathway represent potential therapeutic strategies for pain management. Based on the understanding of the crystal structure, biological functions and its signaling pathway of p38 MAPK, chemically synthesized p38 MAPK inhibitors have become available. Natural products and biological components may also serve as potential p38 MAPK inhibitors. To this end, we will evaluate their potential for chronic pain management.
This chapter will present advances in the treatment of visceral pain. Various treatments for visceral pain have been described in detail in the previous sections (Chaps. 6, 7, 8, and 9), and this chapter will focus on the major discoveries and advances in clinical applications of treatments for visceral pain in recent years.
