THE ROLE OF ENDOGENOUS OPIOIDS IN ENHANCING THE ANTINOCICEPTION PRODUCED BY THE COMBINATION OF DELTA(9)-TETRAHYDROCANNABINOL AND MORPHINE IN THE SPINAL-CORD

We have shown previously that intrathecal (i.t.) administration of the combination of Delta(9)-tetrahydrocannabinal (THC) and morphine resul ts in a greater than additive antinociceptive effect. Similarly, pretr eating mice with subthreshold doses of the kappa agonist, Dynorphin A (1-8), produced a parallel, leftward shift of the morphine dose-respon se curve, shifting the ED(50) of morphine from 0.32 to 0.04 mu g/mouse . A cocktail of enzyme inhibitors used to prevent the metabolism of Dy norphin A (1-8) into the delta receptor agonist, [Leu(5)]-enkephalin, attenuated the enhancement of morphine-induced antinociception by Delt a(9)-THC. The enhanced antinociceptive effect observed after i.t. admi nistration of the combination of Delta(9)-THC and morphine was also at tenuated with antisera to Dynorphin A (1-8) (10 mu g/mouse) and Dynorp hin A (1-13) (10 mu g/mouse). Antisera to Dynorphin A (1-8) and Dynorp hin A (1-17) blocked the antinociceptive effects of Delta(9)-THC (50 m u g i.t.) without producing any significant alteration in the hypother mic and cataleptic effects or hypomotility produced by Delta(9)-THC. T he antinociception produced by the combination of Delta(9)-THC and mor phine was blocked by the kappa antagonist, nor-binaltorphimine (2 mu g /mouse), as well as the delta antagonist, naltrindole (5 mu g/mouse). Thus, the antinociception of morphine, which is mediated predominately by mu receptors, may be enhanced by Delta(9)-THC through the activati on of kappa and delta receptors.