• Fabrice Marger, Agathe Gelot, Abdelkrim Alloui, Julien Matricon, Juan F Sanguesa Ferrer, Christian Barrère, Anne Pizzoccaro, Emilie Muller, Joël Nargeot, Terrance P Snutch, Alain Eschalier, Emmanuel Bourinet, and Denis Ardid.
• Département de Physiologie, Institut de Génomique Fonctionnelle, 34094 Montpellier, France.
• Proc. Natl. Acad. Sci. U.S.A. 2011 Jul 5; 108 (27): 11268-73.

AbstractThe 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(V)3.2 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 Ca(V)3.2 channels and pharmacological blockade with calcium channel antagonists attenuates IBS-like painful symptoms. Mechanistically, butyrate acts to promote the increased insertion of Ca(V)3.2 channels into primary sensory neuron membranes, likely via a posttranslational effect. The butyrate-mediated regulation can be recapitulated with recombinant Ca(V)3.2 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(V)3.2 as a promising target for the development of efficient analgesics for the visceral discomfort and pain associated with IBS.

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