Pathophysiology Of Visceral Pain Research Articles

Local Colonic Administration of a Serine Protease Inhibitor Improves Post-Inflammatory Visceral Hypersensitivity in Rats

Dysregulation of the protease–antiprotease balance in the gastrointestinal tract has been suggested as a mechanism underlying visceral hypersensitivity in conditions such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). We aimed to study the potential therapeutic role of an intracolonically administered serine protease inhibitor for the treatment of abdominal pain in a post-inflammatory rat model for IBS. An enema containing 2,4,6-trinitrobenzene sulfonic acid (TNBS) was used to induce colitis in male Sprague–Dawley rats, whereas controls received a saline solution. Colonoscopies were performed to confirm colitis and follow-up mucosal healing. In the post-inflammatory phase, the serine protease inhibitor UAMC-00050 (0.1–5 mg/kg) or its vehicle alone (5% DMSO in H2O) was administered in the colon. Thirty minutes later, visceral mechanosensitivity to colorectal distensions was quantified by visceromotor responses (VMRs) and local effects on colonic compliance and inflammatory parameters were assessed. Specific proteolytic activities in fecal and colonic samples were measured using fluorogenic substrates. Pharmacokinetic parameters were evaluated using bioanalytical measurements with liquid chromatography–tandem mass spectrometry. Post-inflammatory rats had increased trypsin-like activity in colonic tissue and elevated elastase-like activity in fecal samples compared to controls. Treatment with UAMC-00050 decreased trypsin-like activity in colonic tissue of post-colitis animals. Pharmacokinetic experiments revealed that UAMC-00050 acted locally, being taken up in the bloodstream only minimally after administration. Local administration of UAMC-00050 normalized visceral hypersensitivity. These results support the role of serine proteases in the pathophysiology of visceral pain and the potential of locally administered serine protease inhibitors as clinically relevant therapeutics for the treatment of IBS patients with abdominal pain.

Recent advances in the pathophysiology of visceral pain in irritable bowel syndrome

Recent advances in the pathophysiology of visceral pain in irritable bowel syndrome

Central and Peripheral Mechanism of Acupuncture Analgesia on Visceral Pain: A Systematic Review.

Background/Aims Despite the wide use of acupuncture for the management of visceral pain and the growing interest in the pathophysiology of visceral pain, there is no conclusive elucidation of the mechanisms behind the effects of acupuncture on visceral pain. This systematic review aims to provide an integrative understanding of the treatment mechanism of acupuncture for visceral pain. Methods Electronic and hand searches were conducted to identify studies that involved visceral pain and acupuncture. Results We retrieved 192 articles, out of which 46 studies were included in our review. The results of our review demonstrated that visceral pain behaviors were significantly alleviated in response to acupuncture treatment in groups treated with this intervention compared to in sham acupuncture or no-treatment groups. Changes in the concentrations of β-endorphin, epinephrine, cortisol, and prostaglandin E2 in plasma, the levels of c-Fos, substance P, corticotropin-releasing hormone, P2X3, acetylcholinesterase (AchE), N-methyl-D-aspartate (NMDA) receptors, and serotonin in the gut/spinal cord, and the neuronal activity of the thalamus were associated with acupuncture treatment in visceral pain. Conclusions Acupuncture reduced visceral pain behavior and induced significant changes in neuronal activity as well as in the levels of pain/inflammation-related cytokines and neurotransmitters in the brain-gut axis. Further researches on the thalamus and on a standard animal model are warranted to improve our knowledge on the mechanism of acupuncture that facilitates visceral pain modulation.

Neonatal Maternal Deprivation Followed by Adult Stress Enhances Adrenergic Signaling to Advance Visceral Hypersensitivity

The pathophysiology of visceral pain in patients with irritable bowel syndrome remains largely unknown. Our previous study showed that neonatal maternal deprivation (NMD) does not induce visceral hypersensitivity at the age of 6 weeks in rats. The aim of this study was to determine whether NMD followed by adult stress at the age of 6 weeks induces visceral pain in rats and to investigate the roles of adrenergic signaling in visceral pain. Here we showed that NMD rats exhibited visceral hypersensitivity 6 h and 24 h after the termination of adult multiple stressors (AMSs). The plasma level of norepinephrine was significantly increased in NMD rats after AMSs. Whole-cell patch-clamp recording showed that the excitability of dorsal root ganglion (DRG) neurons from NMD rats with AMSs was remarkably increased. The expression of β2 adrenergic receptors at the protein and mRNA levels was markedly higher in NMD rats with AMSs than in rats with NMD alone. Inhibition of β2 adrenergic receptors with propranolol or butoxamine enhanced the colorectal distention threshold and application of butoxamine also reversed the enhanced hypersensitivity of DRG neurons. Overall, our data demonstrate that AMS induces visceral hypersensitivity in NMD rats, in part due to enhanced NE-β2 adrenergic signaling in DRGs.

The Pharmacology of Visceral Pain.

Visceral pain describes pain emanating from the internal thoracic, pelvic, or abdominal organs. Unlike somatic pain, visceral pain is generally vague, poorly localized, and characterized by hypersensitivity to a stimulus such as organ distension. While current therapeutics provides some relief from somatic pain, drugs used for treatment of chronic visceral pain are typically less efficacious and limited by multiple adverse side effects. Thus, the treatment of visceral pain represents a major unmet medical need. Further, more basic research into the physiology and pathophysiology of visceral pain is needed to provide novel targets for future drug development. In concert with chronic visceral pain, there is a high comorbidity with stress-related psychiatric disorders including anxiety and depression. The mechanisms linking visceral pain with these overlapping comorbidities remain to be elucidated. However, persistent stress facilitates pain perception and sensitizes pain pathways, leading to a feed-forward cycle promoting chronic visceral pain disorders. We will focus on stress-induced exacerbation of chronic visceral pain and provide supporting evidence that centrally acting drugs targeting the pain and stress-responsive brain regions may represent a valid target for the development of novel and effective therapeutics.

Stress-induced visceral pain: toward animal models of irritable-bowel syndrome and associated comorbidities.

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.

Upregulation of Protein Kinase C Gamma in Spinal Cord after Formalin Intracolonic Injection

Visceral pain remains one of the most commonly observed clinical symptoms, and yet, it continues to represent a large unmet therapeutic demand. Work from our lab and others have aimed to describe potential mechanisms underlying the pathophysiology of visceral pain and have identified protein kinase C gamma (PKC γ) as an important molecular target, as it undergoes prominent membrane translocation in visceral pain and directly affects many pain signaling pathways. In this study, we continued our investigation of PKC γ modulation in visceral pain and measured PKC γ expression in the spinal cord at 30, 60, and 120 min following visceral pain that was induced by intracolonic injection of formalin. PKC γ mRNA was significantly increased at 60 min following formalin injection, but not at 30 or 120 min following injection, as detected by reverse transcriptase polymerase chain reaction (RT-PCR). Western blot analysis and immunocytochemistry confirmed the up-regulation of PKC γ protein expression at 60 min following formalin injection. Furthermore, immunocytochemistry also confirmed the localization of PKC γ positive neurons to the superficial layers of the spinal cord dorsal horn, where primary afferent terminals transmitting pain information are received. Taken together, our results implicate an important role for PKC γ in the development of visceral pain.

Experimental endotoxemia as a model to study neuroimmune mechanisms in human visceral pain

The administration of bacterial endotoxin (i.e., lipopolysaccharide, LPS) constitutes a well-established experimental approach to study the effects of an acute and transient immune activation on physiological, behavioral, and emotional aspects of sickness behavior in animals and healthy humans. However, little is known about possible effects of experimental endotoxemia on pain in humans. This knowledge gap is particularly striking in the context of visceral pain in functional as well as chronic-inflammatory gastrointestinal disorders. Although inflammatory processes have been implicated in the pathophysiology of visceral pain, it remains incompletely understood how inflammatory mediators interact with bottom-up (i.e., increased afferent input) and top-down (i.e., altered central pain processing) mechanisms of visceral hyperalgesia. Considering the recent findings of visceral hyperalgesia after LPS application in humans, in this review, we propose that experimental endotoxemia with its complex peripheral and central effects constitutes an experimental model to study neuroimmune communication in human pain research. We summarize and attempt to integrate relevant animal and human studies concerning neuroimmune communication in visceral and somatic pain, discuss putative mechanisms, and conclude with future research directions.

Increased glial glutamate transporter EAAT2 expression reduces visceral nociceptive response in mice

Visceral hypersensitivity is the leading complaint of functional bowel disorders. Central sensitization mediated by glutamate receptor activation is implicated in pathophysiology of visceral pain. The glial glutamate transporter EAAT2 is the principal mediator of glutamate clearance to terminate glutamate-mediated responses. Transgenic mice overexpressing human EAAT2 (EAAT2 mice), which exhibited a twofold enhanced glutamate uptake, showed 39% less writhing response to intraperitoneal acetic acid than nontransgenic littermates. Moreover, EAAT2 transgenic mice showed a 53-64% reduction in visceromotor response (VMR) to colorectal distension (CRD) in assessments of the response to graded increase in pressures. Corroborating the involvement of enhanced glutamate uptake, wild-type mice treated for 1 wk with ceftriaxone, an EAAT2 expression activator, showed a 49-70% reduction in VMR to CRD. Moreover, systemic pretreatment with the selective EAAT2 transporter blocker dihydrokainate reversed the ceftriaxone-blunted nociceptive response to CRD. However, the enhanced VMR to CRD produced by intracolonic ethanol was not significantly attenuated by 1-wk ceftriaxone pretreatment. The data suggest that enhanced glutamate uptake provides protective effects against colonic distension-induced nociception and represents an exciting new mechanistic approach leading to better therapeutic options to visceral pain disorders.

J.J. Bonica lecture—2000: Physiology, pathophysiology, and pharmacology of visceral pain

Background and Objectives: The principal objective of this report is to review recent experimental advances in our understanding of the physiology and pathophysiology of visceral pain and to describe results of studies of opioid modulation of visceral nociception. Methods: Results are drawn from electrophysiological studies of single pelvic nerve afferent fibers innervating the descending colon in the rat. Results: The important findings include the following: identification of a subset of pelvic nerve fibers that likely function to signal acute visceral pain, sensitization of mechanosensitive pelvic nerve fibers, and documentation of the presence of silent nociceptors in the pelvic nerve. With respect to pharmacological modulation of pelvic nerve fiber responses to colonic distension, only kappa-opioid receptor agonists, and not mu- or delta-opioid receptor agonists, were effective. Conclusions: All pelvic nerve fibers innervating the descending colon can be sensitized and contribute to visceral pain; their responses are modulated by kappa-opioid receptor agonists acting in the periphery. Reg Anesth Pain Med 2000;25:632-638.

Pathophysiology of visceral pain

Visceral pain has a temporal evolution. Its first phase is a poorly defined, midline sensation (true visceral pain) that soon becomes referred to a somatic region; there it may manifest with or without hyperalgesia. The pathophysiology of symptoms in the various phases differs. The diffuse localization of true visceral pain is probably due to the low density of visceral sensory innervation and extensive divergence of the visceral input within the central nervous system. Although referred pain without hyperalgesia is attributable to the well-documented convergence of both visceral and somatic afferent inputs onto the same central neurons, referred pain with hyperalgesia is more difficult to explain. Central mechanisms may be involved in the hyperalgesia, in terms of a spinal irritable focus triggered by the visceral barrage, which facilitates messages from somatic structures. The intervention of a reflex mechanism has also been suggested.