LOW-DOSES OF ANANDAMIDES INHIBIT PHARMACOLOGICAL EFFECTS OF DELTA(9)-TETRAHYDROCANNABINOL

It has been shown previously that the endogenous cannabinoid receptor ligand arachidonylethanolamide (anandamide 20:4, n-6) induces in vivo and in vitro effects typical of a cannabinoid partial agonist. We now report that the synthetic docosahexaenytethanolamide (anandamide 22:6, n-3) shows similar activities. In addition we show that these two ana ndamides, under certain experimental conditions, antagonize the effect s of Delta(9)-THC both in vivo and in vitro. Thus a significant decrea se in the potency of Delta(9)-THC-induced inhibition of adenylate cycl ase was observed in N18TG2 neuroblastoma cells that were pretreated wi th low concentrations of anandamides. At these low concentrations of a nandamides had no effect when applied alone. In vivo, Sabra or ICR mic e were subjected to a tetrad of tests, designed to detect cannabinoid- induced effects. Mice pretreated (i.p.) with 10 mg/kg of Delta(9)-THC received injections with anandamides. Only low doses (0.0001-0.1 mg/kg ) of the anandamides, which had no effects when administered alone, pa rtially or fully inhibited the THC-induced effects. These findings sug gest that the inhibition of Delta(9)-THC-induced effects by low doses of anandamides may be due to partial agonistic effects of these materi als. It is possible that low doses of the anandamides are capable of a ctivating a Gs protein mediated signaling pathway, or may cause an all osteric modulation of the cannabinoid receptor.