Antinociceptive effects of cocaine/opioid combinations in rhesus monkeys

This study characterized the antinociceptive effects of cocaine alone and in combination with mu, delta, and kappa opioids in rhesus monkeys. The shaved tails of four rhesus monkeys were exposed to warm water (42, 46, 50, 54, and 58°C), and tail withdrawal latencies (20 sec maximum) from each temperature were determined. The temperature that produced a tail withdrawal latency of 10 sec (T10) was interpolated, and drug-induced changes in the T10 value (ΔT10) were calculated. Dose-dependent increases in ΔT10 were produced by cocaine (0.032-1.8 mg/kg), the high efficacy mu agonist fentanyl (0.001-0.1 mg/kg), the intermediate efficacy mu agonist morphine (0.1-18 mg/kg), the low efficacy mu agonist nalbuphine (1-32 mg/kg), and the kappa agonist U69,593 (0.0032-0.1 mg/kg). The delta agonist BW373U86 (0.56 mg/kg) produced no effect. Relative maximum effects, determined from the maximum ΔT10 values produced by each drug, were fentanyl ≥ (5,7,8β)-N-methyl-N[2- (1-pyrrolidinyl)1-oxaspiro[4,5]dec-8-yl]benzeneacetamide > morphine > nalbuphine ≥ cocaine > BW373U86. When individual doses of cocaine (0.1-1.8 mg/kg) and morphine (0.32-10.0 mg/kg) were combined, cocaine produced a dose- dependent increase in the effects of each dose of morphine, and the antinociceptive effects of most cocaine/morphine combinations were significantly greater than the antinociceptive effects of either cocaine or morphine alone. Cocaine (1.8 mg/kg) was also combined with nalbuphine (1.0, 10 mg/kg), fentanyl (0.001, 0.032 mg/kg), BW373U86 (0.56 mg/kg) and U69,593 (0.0032-0.056 mg/kg). Cocaine/nalbuphine combinations produced effects markedly greater than either drug alone. Cocaine in combination with a low dose of fentanyl (0.001 mg/kg) produced effects equivalent to cocaine alone, whereas cocaine in combination with a high close of fentanyl (0.032 mg/kg) produced effects equivalent to fentanyl alone. The cocaine/BW373U86 combination produced effects identical to cocaine alone. Cocaine/U69,593 combinations produced little or no antinociception, and 1.8 mg/kg cocaine in combination with the highest dose of U69,593 (0.056 mg/kg) produced significantly less antinociceptive effect than either cocaine or U69,593 alone. These findings suggest that, in rhesus monkeys, cocaine enhances the antinociceptive effects of low to medium efficacy mu agonists but not high efficacy mu agonists or BW373U86. In contrast, cocaine and kappa agonists can attenuate each other's antinociceptive effects.