• Amaury Francois, Nicolas Kerckhove, Mathieu Meleine, Abdelkrim Alloui, Christian Barrere, Agathe Gelot, Victor N Uebele, John J Renger, Alain Eschalier, Denis Ardid, and Emmanuel Bourinet.
• Laboratories of Excellence, Ion Channel Science and Therapeutics, Institut de Génomique Fonctionnelle, 141 rue de la Cardonille, 34094 Montpellier, France; CNRS UMR5203, Montpellier, France.
• Pain. 2013 Feb 1;154(2):283-93.

AbstractT-type calcium channels encoded by the Ca(V)3.2 isoform are expressed in nociceptive primary afferent neurons where they contribute to hyperalgesia and thus are considered as a potential therapeutic target to treat pathological pain. Here we report that the small organic state-dependent T-type channel antagonist TTA-A2 efficiently inhibits recombinant and native Ca(V)3.2 currents. Although TTA-A2 is a pan Ca(V)3 blocker, it demonstrates a higher potency for Ca(V)3.2 compared to Ca(V)3.1. TTA-A2 selectivity for T-type currents was demonstrated in sensory neurons where it lowered cell excitability uniquely on neurons expressing T-type channels. In vivo pharmacology in Ca(V)3.2 knockout and wild type mice reveal that TTA-A2-mediated antinociception critically depends on Ca(V)3.2 expression. The pathophysiology of irritable bowel syndrome (IBS) was recently demonstrated to involve Ca(V)3.2 in a rat model of this disease. Oral administration of TTA-A2 produced a dose-dependent reduction of hypersensitivity in an IBS model, demonstrating its therapeutic potential for the treatment of pathological pain. Overall, our results suggest that the high potency of TTA-A2 in the depolarized state strengthen its analgesic efficacy and selectivity toward pathological pain syndromes. This characteristic would be beneficial for the development of analgesics targeting T-type channels, in particular for the treatment of pain associated with IBS.Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

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