The effect of cannabinoid receptor antagonism with SR141716A on antinociception induced by cocaine and the NMDA receptor antagonist, MK-801.
In the rat, antinociception of supraspinal origin is observed in response to administration of cocaine or an antagonist of the NMDA receptor for glutamate. The current study was conducted to determine if endocannabinoids are involved in the antinociceptive effect of cocaine, or antagonism of NMDA receptor binding. Intraperitoneal (i.p.) administration to male rats of cocaine, or the NMDA receptor antagonist, MK-801, resulted in a significant antinociceptive response of supraspinal origin, as indicated by a significant increase in reaction time in the hot plate test of analgesia (increase in the amount of time before the animal reacted to the hot plate by licking its paws or jumping). Treatment with SR141716A, a specific antagonist of the cannabinoid (CB1) receptor, resulted in a complete reversal of cocaine-induced antinociception when administered at a dose of 5.0mg/kg. Although the 2.5 and 5.0mg/kg doses of SR141716A produced a significant reduction in the antinociceptive effect of MK-801, the effect was incomplete since the reaction time in the hot plate test remained greater than that observed in vehicle-treated controls. These findings suggest that activation of the CB1 receptor participates significantly in antinociception resulting from treatment with cocaine and with the NMDA receptor antagonist, MK-801. The partial reversal of the antinociceptive effect of MK-801 by CB1 receptor antagonism indicates other mediators of nociception, in addition to the endocannabinoids, appear to be active in the antinociceptive response to NMDA receptor antagonism.
Forman
Lloyd J
LJ
Department of Cell Biology, School of Osteopathic Medicine, University of Medicine and Dentistry of New Jersey, 2 Medical Center Drive, Stratford, NJ 08084, USA. lloyd.j.forman@umdnj.edu
D000779:Anesthetics, Local / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D063385:Cannabinoid Receptor Modulators; D003042:Cocaine / Q000494:pharmacology* / Q000627:therapeutic use; D016291:Dizocilpine Maleate / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D010146:Pain / Q000503:physiopathology / Q000517:prevention & control; D010147:Pain Measurement / Q000187:drug effects*; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000037:antagonists & inhibitors* / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D000077285:Rimonabant
D000779:Anesthetics, Local; D063385:Cannabinoid Receptor Modulators; D018691:Excitatory Amino Acid Antagonists; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D003042:Cocaine; D000077285:Rimonabant