Visceral hypersensitivity in irritable bowel syndrome: molecular mechanisms and therapeutic agents

A. Akbar, J.R.F. Walters, S. Ghosh

Disclosures

Aliment Pharmacol Ther. 2009;30(5):423-435. 

In This Article

Abstract and Introduction

Abstract

Background: Although development of visceral pain is an important defensive mechanism, hypersensitivity results in a significant clinical problem and is likely to be one of the major factors involved in the pathogenesis of abdominal and chest pain in functional bowel disorders (FBDs). Understanding of the molecular mechanisms involved in peripheral sensitization of visceral nociceptors has advanced as a result of the experimental studies, especially in animal models, which have led to knowledge and identification of key mediators and receptors.
Aim: To provide a comprehensive review focused on the peripheral mechanisms believed to be responsible for sensitization and potential molecular targets for a disorder which is common, distressing and has sub-optimal treatment options.
Methods: Literature review using Ovid and Pubmed from 1966.
Results: There is substantial interest in the development of new drugs for treatment of FBDs in the background of advances in understanding the molecular and physiological mechanisms of visceral hypersensitivity. The potential drug targets include TPRV1, ASICs, voltage-gated sodium channels, ATP, PAR-2, cannabinoid, prostaglandin, tachykinin and 5HT3 receptors.
Conclusion: It is anticipated that with advancing molecular understanding of the basis of visceral hypersensitivity, the next decade will see accelerated development of new molecules for treatment of functional bowel diseases.

Introduction

Irritable bowel syndrome (IBS) is the most common disorder presenting to gastroenterologists, with a prevalence of up to 20% in the United Kingdom and the United States of America[1,2] and accounting for 40 – 60% of referrals to gastroenterology outpatient clinics.[3] Patients commonly present with abdominal pain associated with altered bowel habit. Self-reported abdominal pain is a very common symptom in the population including healthy individuals, but pain is more severe and frequent in patients with IBS.[4] This is associated with an abnormal bowel function where the normal relationship between stool form and symptoms such as urgency, straining and feeling of incomplete evacuation become distorted.[5] Untreated pain leads to a decrease in daily function capability, social stresses, loss of work and poor quality of life.[6] Furthermore, a study carried out by Sandler et al.[7] revealed that abdominal pain was the symptom most likely to result in medical consultation in IBS patients. Therapeutic options currently available are limited and often disappointing in efficacy with most agents aimed at control of symptoms. Functional bowel disorders such as IBS are characterized by visceral hypersensitivity[8] defined by reduced pain and discomfort thresholds,[9,10] which may manifest as pain associated with bowel disturbances.[5] Although the pathogenesis of visceral hypersensitivity is not fully understood, several mechanisms have been proposed including subtle inflammation, psychosocial factors and altered sensorimotor function of the gut, a major component of which is believed to be peripheral and central sensitization of visceral afferent neuronal pathways (Figure 1).[11] Similarly, the other functional bowel disorders such as noncardiac chest pain, functional dyspepsia and functional abdominal pain present commonly and treatment of these disorders can be challenging.

Figure 1.

The Pathogenesis of Visceral Hypersensitivity

Further knowledge of receptors and neurotransmitters and receptors involved in visceral pain is beginning to provide a foundation for new pharmacology development in this difficult area, with signal transduction, transmission, modulation and perception all potential therapeutic targets ( Table I ).

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