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The Journal of Neuroscience, November 5, 2008, 28(45):11593-11602; doi:10.1523/JNEUROSCI.3322-08.2008

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Behavioral/Systems/Cognitive
Constitutive Activity at the Cannabinoid CB₁ Receptor Is Required for Behavioral Response to Noxious Chemical Stimulation of TRPV1: Antinociceptive Actions of CB1 Inverse Agonists

Beatriz Fioravanti,^1,2 Milena De Felice,^1,2 Cheryl L. Stucky,³ Karen A. Medler,³ Miaw-Chyi Luo,^1,2 Luis R. Gardell,^1,2 Mohab Ibrahim,^1,2 T. Phil Malan Jr,^1,2 Henry I. Yamamura,^1,2  Michael H. Ossipov,^1,2 Tamara King,^1,2 Josephine Lai,^1,2 Frank Porreca,^1,2 and Todd W. Vanderah^1,2

Departments of ¹Pharmacology and ²Anesthesiology, College of Medicine, University of Arizona, Tucson, Arizona 85724, and ³Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53226-0509

Correspondence should be addressed to Dr. Todd W. Vanderah, Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724. Email: vanderah{at}u.arizona.edu

The potential modulation of TRPV1 nociceptive activity by the CB₁ receptor was investigated here using CB₁ wild-type (WT) and knock-out (KO) mice as well as selective CB₁ inverse agonists. No significant differences were detected in baseline thermal thresholds of ICR, CB₁WT or CB₁KO mice. Intraplantar capsaicin produced dose- and time-related paw flinch responses in ICR and CB₁WT mice and induced plasma extravasation yet minimal responses were seen in CB₁KO animals with no apparent differences in TRPV1 channel expression. Capsaicin-evoked CGRP release from spinal cord tissue and capsaicin-evoked action potentials on isolated skin-nerve preparation were significantly decreased in CB₁KO mice. Pretreatment with intraplantar galanin and bradykinin, compounds known to sensitize TRPV1 receptors, restored capsaicin-induced flinching in CB₁KO mice. The possibility that constitutive activity at the CB₁ receptor is required to maintain the TRPV1 receptor in a "sensitized" state was tested using CB₁ inverse agonists. The CB₁ inverse agonists elicited concentration-related inhibition of capsaicin-induced calcium influx in F-11 cells and produced dose-related inhibition of capsaicin-induced flinching in ICR mice. These data suggest that constitutive activity at the CB₁ receptor maintains the TRPV1 channel in a sensitized state responsive to noxious chemical stimuli. Treatment with CB₁ inverse agonists may promote desensitization of the channel resulting in antinociceptive actions against chemical stimulus modalities. These studies propose possible therapeutic exploitation of a novel mechanism providing pain relief by CB₁ inverse agonists.

Key words: TRPV1; CB1; capsaicin; pain; phospholipase C; knock-out mouse

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Received July 14, 2008; revised Sept. 26, 2008; accepted Sept. 28, 2008.

Correspondence should be addressed to Dr. Todd W. Vanderah, Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724. Email: vanderah{at}u.arizona.edu

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