Abstract
Chronic visceral pain represents a major unmet clinical need with the severity of pain ranging from mild to so severe as to prevent individuals from participating in day-to-day activities and detrimentally affecting their quality of life. Although chronic visceral pain can be multifactorial with many different biological and psychological systems contributing to the onset and severity of symptoms, one of the major triggers for visceral pain is the exposure to emotional and physical stress. Chronic visceral pain that is worsened by stress is a hallmark feature of functional gastrointestinal disorders such as irritable bowel syndrome (IBS). Current pharmacological interventions for patients with chronic visceral pain generally lack efficacy and many are fraught with unwanted side effects. Cognitive behavioral therapy (CBT) has emerged as a psychotherapy that shows efficacy at ameliorating stress-induced chronic visceral pain; however, the molecular mechanisms underlying CBT remain incompletely understood. Preclinical studies in experimental models of stress-induced visceral pain employing environmental enrichment (EE) as an animal model surrogate for CBT are unraveling the mechanism by which environmental signals can lead to long-lasting changes in gene expression and behavior. Evidence suggests that EE signaling interacts with stress and nociceptive signaling. This review will (1) critically evaluate the behavioral and molecular changes that lead to chronic pain in IBS, (2) summarize the pharmacological and non-pharmacological approaches used to treat IBS patients, and (3) provide experimental evidence supporting the potential mechanisms by which CBT ameliorates stress-induced visceral pain.
Highlights
Irritable bowel syndrome (IBS) is a chronic gastrointestinal (GI) disorder that affects about 10– 20% of the population of the USA [1]
Experimental models of post-inflammatory IBS have revealed that previous inflammatory insult in the colon of rodents sensitizes afferent neurons to induce visceral hypersensitivity mediated by increased expression of nociceptive receptors including calcitonin gene-related peptide (CGRP) [35] and transient receptor potential cation channel subfamily V member 1 (TrpV1) [36] in the dorsal root ganglia cells [37, 38] leading to enhanced nociceptive transmission
Anxiety, and inflammation cause changes in the expression of genes (GR, corticotropinreleasing hormone (CRH), and TRPV1) in brain centers critical for stress reactivity and sensory neurotransmission. These alterations potentiate stress reactivity and sensitize nociceptive afferent fibers leading to visceral hypersensitivity in IBS
Summary
Irritable bowel syndrome (IBS) is a chronic gastrointestinal (GI) disorder that affects about 10– 20% of the population of the USA [1]. Experimental models of post-inflammatory IBS have revealed that previous inflammatory insult in the colon of rodents sensitizes afferent neurons to induce visceral hypersensitivity mediated by increased expression of nociceptive receptors including calcitonin gene-related peptide (CGRP) [35] and transient receptor potential cation channel subfamily V member 1 (TrpV1) [36] in the dorsal root ganglia cells [37, 38] leading to enhanced nociceptive transmission Taken together, these studies demonstrate that changes in the processing of sensory signals in the central and peripheral nervous systems contribute to the pathophysiology of chronic visceral pain. Animal models of mood and depression disorders suggest exposure to EE improves recovery from and decreases anxiety-like symptoms due to restraint and social defeat stress via hippocampal [114] and amygdalar [115] dependent mechanisms, respectively. EE prevented the stress-induced decrease in GR expression in the CeA and inhibited CRH-induced potentiation of the stress response to block the development of visceral hypersensitivity [20]
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