T-type calcium channels contribute to colonic hypersensitivity in a rat model of irritable bowel syndrome

Abstract

The symptoms of irritable bowel syndrome (IBS) include significant abdominal pain and bloating. Current treatments are empirical and often poorly efficacious, and there is a need for the development of new and efficient analgesics aimed at IBS patients. T-type calcium channels have previously been validated as a potential target to treat certain neuropathic pain pathologies. Here we report that T-type calcium channels encoded by the Ca V3.2 isoform are expressed in colonic nociceptive primary afferent neurons and that they contribute to the exaggerated pain perception in a butyratemediated rodent model of IBS. Both the selective genetic inhibition of Ca V3.2 channels and pharmacological blockade with calcium channel antagonists attenuates IBS-like painful symptoms. Mechanistically, butyrate acts to promote the increased insertion of Ca V3.2 channels into primary sensory neuron membranes, likely via a post-translational effect. The butyrate-mediated regulation can be recapitulated with recombinant Ca V3.2 channels expressed in HEK cells and may provide a convenient in vitro screening system for the identification of T-type channel blockers relevant to visceral pain. These results implicate T-type calcium channels in the pathophysiology of chronic visceral pain and suggest Ca V3.2 as a promising target for the development of efficient analgesics for the visceral discomfort and pain associated with IBS.