Irritable Bowel Syndrome Clinical Care Gaps and the Potential of Future Therapeutics Based on Peripheral Visceral Afferent Modulation.

Current management of irritable bowel syndrome (IBS) is focused on bowel dysfunction or central neuromodulators. The aims of this review were to: appraise unmet needs in IBS treatment; review the physiology of visceral afferent functions and specifically receptors in the dorsal root ganglion (DRG) cell bodies of the first order neurones; and summarize evidence of efficacy of pharmacological approaches directed at receptors expressed by DRGs based on rodent models of visceral hypersensitivity and randomized controlled trials in IBS. A literature search was done using terms identified in the aims section. The greatest need in IBS is safe treatment of pain. Physiological and noxious stimuli are conducted to the brain through vagal and pelvic parasympathetic pathways, and noxious stimuli through visceral afferents and spinal cord. Peripheral visceral afferents, with cell bodies in DRG, have receptors targeted pharmacologically to relieve pain (or surrogates) in rodent IBS models of visceral hypersensitivity. Advances in understanding mechanisms of visceral hypersensitivity lead to consideration of targeting receptors on the DRG. Those receptors on DRGs are also expressed in the central nervous system and include α-2 adrenergic, somatostatin-SS2, 5-HT3, cannabinoid, α4β2 and α6β2 nicotininc cholinergic, calcitonin gene-related peptide, κ-opioid and glucagon-like peptide 1 receptors and acid-gated ion channels. Evidence from predominantly pre-clinical and human studies supporting these peripheral targets is summarized, and provides the rationale to develop novel, peripherally restricted pharmaceuticals to reduce visceral pain in IBS. Novel neuromodulators restricted to peripheral actions and targeting DRG receptors would constitute a novel alternative to central neuromodulators for IBS pain, in addition to potential effects on colonic transit or secretion.