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

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.