Journal Article

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

Barrère, Christian, Snutch, Terrance P., Eschalier, Alain, Nargeot, Joël, Marger, Fabrice, Ardid, Denis, Muller, Emilie, Bourinet, Emmanuel, Pizzoccaro, Anne, Alloui, Abdelkrim, Matricon, Julien, Ferrer, Juan F. Sanguesa, Gelot, Agathe

2011

Overview

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 Cav3.2 isoform are expressed in colonic nociceptive primary afferent neurons and that they contribute to the exaggerated pain perception in a butyrate-mediated rodent model of IBS. Both the selective genetic inhibition of Cav3.2 channels and pharmacological blockade with calcium channel antagonists attenuates IBS-like painful symptoms. Mechanistically, butyrate acts to promote the increased insertion of Cav3.2 channels into primary sensory neuron membranes, likely via a post-translational effect. The butyrate-mediated regulation can be recapitulated with recombinant Cav3.2 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 Cav3.2 as a promising target for the development of efficient analgesics for the visceral discomfort and pain associated with IBS.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Analgesics / animal models / Animals / Antagonists / Base Sequence / Biological Sciences / Butyrates / Butyrates - toxicity / Calcium Channel Blockers / Calcium Channel Blockers - pharmacology / Calcium channels / Calcium channels (voltage-gated) / Calcium Channels, T-Type / Calcium Channels, T-Type - deficiency / Calcium Channels, T-Type - genetics / Calcium Channels, T-Type - physiology / Colon / Colon - innervation / Colon - physiopathology / Current density / Disease Models, Animal / Electrophysiological Phenomena / Gene Knockdown Techniques / Hypersensitivity / Insertion / Irritable Bowel Syndrome / Irritable Bowel Syndrome - chemically induced / Irritable Bowel Syndrome - drug therapy / Irritable Bowel Syndrome - physiopathology / Life Sciences / Male / Neuralgia / Neuralgia - drug therapy / Neuralgia - physiopathology / Neurons / Neuropathy / Nociceptors / Nociceptors - physiology / Pain / Pain Perception / Pain Perception - physiology / pathophysiology / patients / Pharmacology / Physiology / Rats / Rats, Sprague-Dawley / RNA, Small Interfering / RNA, Small Interfering - genetics / Rodents / screening / Sensory neurons / T type calcium channels / Vehicles