INHIBITION OF OPIOID-DEGRADING ENZYMES POTENTIATES DELTA(9)-TETRAHYDROCANNABINOL-INDUCED ANTINOCICEPTION IN MICE

Delta(9)-Tetrahydrocannabinol (Delta(9)-THC) elicits antinociception i n rodents through the central CB1 cannabinoid receptor subtype. In add ition, Delta(9)-THC stimulates the release of dynorphin-related peptid es leading to kappa-opioid spinal antinociception. In this work we des cribe the effect of a mixture of thiorphan (a neutral endopeptidase EC 3.4.24.11 inhibitor) and bestatin (an aminopeptidase inhibitor), admin istered i.c.v., on the antinociceptive effect of peripherally administ ered Delta(9)-THC in mice. As in the case of morphine or DAMGO ([D-Ala (2),N-Me-Phe(4),Gly-ol]enkephalin), a mu-selective opioid receptor ago nist, the mixture of enkephalin-degrading enzyme inhibitors also enhan ced the antinociceptive effect of Delta(9)-THC. This effect was blocke d by the CB1 cannabinoid receptor antagonist, SR-141,716-A, as well as by naloxone. The kappa-opioid receptor antagonist nor-binaltorphimine , administered i.t., also antagonized the effect of this combination. Similar results were obtained with the mu-opioid receptor antagonist b eta-funaltrexamine after i.c.v. administration. These results demonstr ate the involvement of both mu-opioid supraspinal and kappa-opioid spi nal receptors in the interaction of both opioid and cannabinoid system s regulating nociception in mice. (C) 1998 Elsevier Science Ltd. All r ights reserved.