Differential blockade of the antinociceptive effects of centrally administered cannabinoids by SR141716A.
We evaluated delta-9 tetrahydrocannabinol (Delta9-THC), delta-8 tetrahydrocannabinol (Delta8-THC), CP55,940 (CP55), 1-deoxy-11-hydroxy-Delta8-THC-dimethylheptyl (deoxy-HU210, a CB2-selective cannabinoid that also binds the CB1 receptor) and the endogenous cannabinoid anandamide (ANA) via i.c.v. and/or intrathecal (i.t.) routes of administration, alone and in combination with SR141716A (SR), a CB1 antagonist, using the tail-flick test. Our studies were performed in order better to characterize potential diversity in interactions of the cannabinoids with the cannabinoid (CB1) receptor. When SR was administered i.c.v. or i.p. before Delta9-THC, Delta8-THC or CP55 (i.c.v. or i.t.), SR was a potent antagonist and the blockade was complete (AD50 </= 8.1 microgram/mouse i.c.v. or AD50 </= 1.4 mg/kg i.p.). The AD50 values (dose of antagonist that produced a 50% antagonism of agonist effects) for blockade of Delta9-THC, Delta8-THC, CP55,940 (i.c.v. or i.t.) by SR (i.c.v. or i.p.) differed significantly for only two combinations [Delta8-THC/SR, both i.c.v. and CP55 (i.t.)/SR (i.p.)]. Conversely, SR (i.t.) produced an incomplete block of the antinociceptive effects of i.t. Delta9-THC, Delta8-THC and CP55 (AD50 = 28.6, 50.2 and 20.9 microgram/mouse, respectively). Blockade of the deoxy-HU210 (i.c.v.) by SR (either i.c.v. or i.p.) was incomplete and AD50 values could not be calculated. Although the maximal blockade of deoxy-HU210 (i.t.) by SR (i.t.) was only 50%, SR administered i.p. before deoxy-HU210 (i.t.) produced a potent and complete blockade (AD50 = 0.4 mg/kg). The effects of SR on ANA-induced antinociception were mixed. The maximal attenuation of the ANA (i.t.) by SR (i.t.) was 38%. SR (i.p.) blockade of ANA was complete, but the AD50 was 15.4 mg/kg, greater than 15-fold higher than that required to block Delta9-THC, Delta8-THC, CP55 or deoxy-HU210. In addition, SR (i.p. or i.t.) failed to block the hypothermic effects of ANA (i.t.), while completely reversing the hypothermic effects of Delta9-THC (i.t.). These data indicate that SR has a much greater efficacy at supraspinal than at spinal sites. Alternatively, such data suggest either a differential interaction of the cannabinoids at the CB1 receptor or the existence of subtypes of the CB1 receptor.
Welch
S P
SP
Department of Pharmacology and Toxicology, Medical College of Virginia/Virginia Commonwealth University, Richmond, Virginia, USA.
Huffman
J W
JW
Lowe
J
J
D000700:Analgesics / Q000037:antagonists & inhibitors*; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects; D002186:Cannabinoids / Q000037:antagonists & inhibitors*; D004399:Dynorphins / Q000378:metabolism; D063388:Endocannabinoids; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010880:Piperidines / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles / Q000494:pharmacology*; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000037:antagonists & inhibitors / Q000187:drug effects; D000077285:Rimonabant; D013116:Spinal Cord / Q000187:drug effects
D000700:Analgesics; D001095:Arachidonic Acids; D002186:Cannabinoids; D063388:Endocannabinoids; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D004399:Dynorphins; D000077285:Rimonabant; C078814:anandamide