Modulation of rat brain opioid receptors by cannabinoids

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 241; no. 2; pp. 534 - 539
• Main Authors: VAYSSE, P. J.-J, GARDNER, E. L, ZUKIN, R. S
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01.05.1987
• Subjects: Animals; Biological and medical sciences; cannabinoids; Cannabinoids - pharmacology; Cyclazocine - analogs & derivatives; Cyclazocine - metabolism; Dihydromorphine - metabolism; Dose-Response Relationship, Drug; Dronabinol - pharmacology; Drug addictions; Enkephalin, D-Penicillamine (2,5); Enkephalins - metabolism; Ethylketocyclazocine; Etorphine - metabolism; Male; Medical sciences; Naloxone - metabolism; neurons; opioids; Rats; Rats, Inbred Strains; Receptors, Opioid - metabolism; Spiperone - metabolism; tetrahydrocannabinol; Toxicology; Opiate receptor; Brain; Vertebrata; Mammalia; Rat; Animal; Interaction; Rodentia; Nervous system; Drug of abuse; Cannabinoid; In vitro
• ISSN: 0022-3565; 1521-0103

The interaction of delta 9-tetrahydrocannabinol (delta 9-THC) and related cannabinoids with opioid receptors of neuronal membranes has been investigated. Treatment of membranes with delta 9-THC consistently decreased specific in vitro binding of [3H]dihydromorphine (mu opioid) in a dose-dependent fashion. Similar dose-dependent changes were elicited by cannabidiol and (+/-)-hexahydrocannabinol. Equilibrium binding studies in which brain membranes were titrated with [3H]dihydromorphine in the presence of delta 9-THC demonstrated that the decrease in [3H]dihydromorphine binding is due to a reduction in the number of binding sites, with no significant alteration in receptor affinity. This result suggests that the interaction of delta 9-THC with opioid receptors is a noncompetitive one. Delta 9-THC also inhibited the binding of the delta opioid [3H]D-Pen2, D-Pen5-enkephalin and the opioid antagonist [3H]naloxone (Ki = 16 and 19 microM, respectively) but failed to inhibit the binding of the kappa opioid [3H]ethylketocyclazocine (after suppression of mu and delta receptor binding), the phencyclidine analog [3H]N-(1-[2-theinyl]cyclohexyl)piperidine, the dopamine antagonist [3H]spiroperidol or the muscarinic antagonist [3H]quinuclidinyl benzilate. Moreover, delta 9-THC inhibited the binding of [3H]etorphine (potent opioid agonist) to solubilized, partially purified opioid receptors with a Ki value similar to that observed for the membrane-bound receptors. This finding indicates that the allosteric modulation of the opioid receptor by delta 9-THC is the result of a direct interaction with the receptor protein or with a specific protein-lipid complex and not merely the result of a perturbation of the lipid bilayer of the membrane.