Modulation of rat brain opioid receptors by cannabinoids
Vaysse, P.J.; Gardner, E.L.; Zukin, R.S.
Journal of Pharmacology and Experimental Therapeutics 241(2): 534-539
1987
ISSN/ISBN: 0022-3565 PMID: 3033219 Document Number: 290663
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 .mu.M, 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-thienyl]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. Finally, the relative potency of several cannabinoids in inhibiting the binding of dihydromorphine was determined. Results from this study showed .DELTA.9-THC to be the most potent noncompetitive inhibitor of the mu receptor; the actual Ki value for .DELTA.9-THC is 3 .+-. 1 .mu.M. Together, these results indicate that .DELTA.9-THC at a pharamacologically relevant concentration modulates mu and delta opioid receptors in a noncompetitive manner.