Multiple roles for NaV1.9 in visceral afferent activation by noxious mechanical and inflammatory stimuli.

Abstract

Chronic visceral pain affects millions of individuals worldwide, remains poorly understood, and current therapeutics are constrained by undesirable adverse events. Inflammation and distension of visceral organs are common causes of pain, suggesting drugs targeting these signalling pathways may be efficacious visceral treatments. The voltage-gated sodium channel subtype 1.9 (NaV1.9) has been strongly associated with the development of inflammatory pain by rodent studies and more recently, by the identification of channelopathies in man. The aim of these studies was to investigate the role of NaV1.9 in visceral afferent signalling in the gut. Data from this thesis demonstrates that NaV1.9 is expressed by approximately half of gut-projecting rodent dorsal root ganglia sensory neurons. Consistent with significant expression in visceral afferents, NaV1.9 is required for normal mechanosensation, and for the direct excitation and mechanical hypersensitisation of mouse colonic afferents by inflammatory mediators applied as an inflammatory soup (bradykinin, ATP, histamine, PGE2, and 5HT) or derived from man (as inflammatory bowel disease tissue supernatants). Additionally, the importance of P2Y receptor activation in both rodent and human gut to algogenic purinergic signalling was demonstrated. Collectively, these results demonstrate that NaV1.9, is required for persistence of responses to intense mechanical stimulation, contributes to inflammatory mechanical hypersensitivity, and is essential for activation by noxious inflammatory mediators, including those from diseased human bowel. These findings suggest that NaV1.9 represents a high-value target for development of visceral analgesics.