期刊
PAIN
卷 154, 期 2, 页码 283-293出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1016/j.pain.2012.10.023
关键词
Analgesia; Colonic hypersensitivity; IBS; Somatic pain; T-type calcium channel
资金
- ANR [ANR-09-MNPS-037, ANR-08-NMPS-025]
- Institut UPSA de la Douleur
- AFM [AFM-12-PainT]
- French Ministry of Research and education
T-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. (c) 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
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