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J Neurosci ; 28(45): 11593-602, 2008 Nov 05.
Article in English | MEDLINE | ID: mdl-18987195

ABSTRACT

The potential modulation of TRPV1 nociceptive activity by the CB(1) receptor was investigated here using CB(1) wild-type (WT) and knock-out (KO) mice as well as selective CB(1) inverse agonists. No significant differences were detected in baseline thermal thresholds of ICR, CB(1)WT or CB(1)KO mice. Intraplantar capsaicin produced dose- and time-related paw flinch responses in ICR and CB(1)WT mice and induced plasma extravasation yet minimal responses were seen in CB(1)KO 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 CB(1)KO mice. Pretreatment with intraplantar galanin and bradykinin, compounds known to sensitize TRPV1 receptors, restored capsaicin-induced flinching in CB(1)KO mice. The possibility that constitutive activity at the CB(1) receptor is required to maintain the TRPV1 receptor in a "sensitized" state was tested using CB(1) inverse agonists. The CB(1) 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 CB(1) receptor maintains the TRPV1 channel in a sensitized state responsive to noxious chemical stimuli. Treatment with CB(1) 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 CB(1) inverse agonists.


Subject(s)
Pain/physiopathology , Receptor, Cannabinoid, CB1/physiology , TRPV Cation Channels/metabolism , Analysis of Variance , Animals , Behavior, Animal/drug effects , Bradykinin/pharmacology , Calcitonin Gene-Related Peptide/metabolism , Calcium/metabolism , Capsaicin/adverse effects , Cell Line, Tumor , Dose-Response Relationship, Drug , Galanin/pharmacology , Gene Expression Regulation/drug effects , Gene Expression Regulation/genetics , Male , Mice , Mice, Inbred ICR , Mice, Knockout , Morphine/therapeutic use , Narcotics/therapeutic use , Nerve Fibers, Unmyelinated/drug effects , Nerve Fibers, Unmyelinated/physiology , Neuroblastoma , Pain/chemically induced , Pain/drug therapy , Pain Measurement , Pain Threshold/drug effects , Pain Threshold/physiology , Piperidines/pharmacology , Pyrazoles/pharmacology , Rats , Reaction Time/drug effects , Receptor, Cannabinoid, CB1/agonists , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Receptor, Cannabinoid, CB1/deficiency , Rimonabant , Stimulation, Chemical , Sulfonamides/pharmacology
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