Mode of potentiating action of cocaine in morphine analgesia

The mechanism of antinociceptive interactions among morphine, cocaine and alcohol was studied in mice, guinea pigs and rabbits. In the tail-pressure test in mice, cocaine and alcohol alone showed almost no antinociceptive effects at doses up to 8 mg/kg, s.c., and 4 g/kg, respectively. Alcohol at 2 g/kg, i.g., also did not influence the effect of morphine, while cocaine at 4 mg/kg, s.c., significantly potentiated the antinociceptive effects of not only morphine but also pentazocine. In an analysis of serum and brain concentration levels of morphine in mice, when morphine and cocaine were simultaneously administered at 2 mg/kg, s.c., and 4 mg/kg, s.c., respectively, both serum and brain levels of morphine showed neither increase nor decrease in comparison with the levels in mice administered morphine alone. In myenteric plexus-longitudinal muscle preparations of isolated guinea pig ileum, 1 microM cocaine enhanced the agonistic effects of both pentazocine and ethylketocyclazocine. Furthermore, cocaine as well as ethylketocyclazocine showed naloxone-reversible agonistic effects in isolated rabbit vas deferens. These results indicate that cocaine may potentiate the antinociceptive effects of morphine and pentazocine by acting on the kappa-opioid receptors as an agonist.