HYPOACTIVITY OF THE SPINAL CANNABINOID SYSTEM RESULTS IN NMDA-DEPENDENT HYPERALGESIA

Cannabinoids, such as Delta(9)-THC, are capable of inhibiting nocicept ion, i.e., pain transmission, at least in part, by interacting with sp inal G(i)/G(o)-coupled cannabinoid receptors. What is not known, howev er, is the antinociceptive role of endogenous spinal cannabinoids. If endogenous cannabinoids modulate basal nociceptive thresholds, then al terations in this system could be involved in the etiology of certain pain states. In this report we provide evidence for tonic modulation o f basal thermal nociceptive thresholds by the spinal cannabinoid syste m. Administration of oligonucleotides directed against CB1 cannabinoid receptor mRNA significantly reduced spinal cannabinoid binding sites and produced significant hyperalgesia when compared with a randomer ol igonucleotide control. A second method used to reduce activity of the spinal cannabinoid receptor was intrathecal administration of the cann abinoid receptor antagonist SR 141716A. SR 141716A evoked thermal hype ralgesia with an ED50 of 0.0012 fmol. The SR 141716A-induced hyperalge sia was dose-dependently blocked by the administration of D-AP-5 or MK -801, two antagonists to the NMDA receptor. These results indicate tha t there is tonic activation of the spinal cannabinoid system under nor mal conditions. Furthermore, hypoactivity of the spinal cannabinoid sy stem results in an NMDA-dependent hyperalgesia and thus may participat e in the etiology of certain chronic pain states.