title: 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(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.
authors.affiliation: Département de Physiologie, Institut de Génomique Fonctionnelle, 34094 Montpellier, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Marger
authors.forename: Agathe
authors.initials: A
authors.lastname: Gelot
authors.forename: Abdelkrim
authors.initials: A
authors.lastname: Alloui
authors.forename: Julien
authors.initials: J
authors.lastname: Matricon
authors.forename: Juan F Sanguesa
authors.initials: JF
authors.lastname: Ferrer
authors.forename: Christian
authors.initials: C
authors.lastname: Barrère
authors.forename: Anne
authors.initials: A
authors.lastname: Pizzoccaro
authors.forename: Emilie
authors.initials: E
authors.lastname: Muller
authors.forename: Joël
authors.initials: J
authors.lastname: Nargeot
authors.forename: Terrance P
authors.initials: TP
authors.lastname: Snutch
authors.forename: Alain
authors.initials: A
authors.lastname: Eschalier
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Bourinet
authors.forename: Denis
authors.initials: D
authors.lastname: Ardid
mesh_terms: D000818:Animals; D001483:Base Sequence; D002087:Butyrates / Q000633:toxicity; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020747:Calcium Channels, T-Type / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D003106:Colon / Q000294:innervation* / Q000503:physiopathology*; D004195:Disease Models, Animal; D055724:Electrophysiological Phenomena; D055785:Gene Knockdown Techniques; D043183:Irritable Bowel Syndrome / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D008297:Male; D009437:Neuralgia / Q000188:drug therapy / Q000503:physiopathology; D009619:Nociceptors / Q000502:physiology; D058748:Pain Perception / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002087:Butyrates; C509958:Cacna1h protein, rat; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D034741:RNA, Small Interfering