Potentiation of delta 9-tetrahydrocannabinol-induced analgesia by morphine in mice: involvement of mu- and kappa-opioid receptors.

The antinociceptive effect of peripheral delta 9-tetrahydrocannabinol was examined in mice previously treated with an inactive dose of morphine. The ED50 of delta 9-tetrahydrocannabinol was significantly reduced by morphine, both in the tail-flick test (0.85 vs. 2.10 mg/kg) and in the hot-plate test (1.51 vs. 4.71 mg/kg and 0.73 vs. 2.47 mg/kg in jumping and paw-lick responses, respectively). The synergistic effect between morphine and delta 9-tetrahydrocannabinol was partially blocked by the cannabinoid receptor antagonist, SR-141,716 A [(N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichorophenyl)-4-methyl-3 -pyrazolecarboxamide, hydrochloride)], at a dose of 2 mg/kg (i.p.) as well as by the opioid receptor antagonist naloxone, at the dose of 1 mg/kg (s.c.). Such an effect was also blocked by i.t. nor-binaltorphimine (a kappa-selective opioid receptor antagonist) given at 20 micrograms/mouse as well as by beta-funaltrexamine (a mu-selective opioid receptor antagonist) at a dose of 2 nmol/mouse (i.c.v., 24 h before the test). Accordingly, the mu-opioid receptor agonist DAMGO ([D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin) potentiated the effect of delta 9-tetrahydrocannabinol. These data show that the synergism between morphine and delta 9-tetrahydrocannabinol appears to involve cannabinoid as well as mu-supraspinal and kappa-spinal opioid receptors.