Peripheral K_V7 channels regulate visceral sensory function in mouse and human colon

Abstract

Background Chronic visceral pain is a defining symptom of many gastrointestinal disorders. The K_V7 family (K_V7.1-K_V7.5) of voltage-gated potassium channels mediates the M current that regulates excitability in peripheral sensory nociceptors and central pain pathways. Here, we use a combination of immunohistochemistry, gut-nerve electrophysiological recordings in both mouse and human tissues, and single-cell qualitative real-time polymerase chain reaction of gut-projecting sensory neurons, to investigate the contribution of peripheral K_V7 channels to visceral nociception. Results Immunohistochemical staining of mouse colon revealed labelling of K_V7 subtypes (K_V7.3 and K_V7.5) with CGRP around intrinsic enteric neurons of the myenteric plexuses and within extrinsic sensory fibres along mesenteric blood vessels. Treatment with the K_V7 opener retigabine almost completely abolished visceral afferent firing evoked by the algogen bradykinin, in agreement with significant co-expression of mRNA transcripts by single-cell qualitative real-time polymerase chain reaction for KCNQ subtypes and the B₂ bradykinin receptor in retrogradely labelled extrinsic sensory neurons from the colon. Retigabine also attenuated responses to mechanical stimulation of the bowel following noxious distension (0-80 mmHg) in a concentration-dependent manner, whereas the K_V7 blocker XE991 potentiated such responses. In human bowel tissues, K_V7.3 and K_V7.5 were expressed in neuronal varicosities co-labelled with synaptophysin and CGRP, and retigabine inhibited bradykinin-induced afferent activation in afferent recordings from human colon. Conclusions We show that K_V7 channels contribute to the sensitivity of visceral sensory neurons to noxious chemical and mechanical stimuli in both mouse and human gut tissues. As such, peripherally restricted K_V7 openers may represent a viable therapeutic modality for the treatment of gastrointestinal pathologies.