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 CB ₁ 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 CB ₁ 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.