A novel delta opioid agonist, BW373U86, in squirrel monkeys responding under a schedule of shock titration

The squirrel monkey titration procedure was used to assess the antinociceptive effects of the novel delta opioid agonist (+/-)-4-(a-R*)-a(2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxyb enzyl)- N,N-diethylbenzamide (BW373U86). Under this procedure shock increased every 15 sec from 0.01 to 2.0 mA in 30 steps. Five responses terminated the shock for 15 sec, after which the shock resumed at a lower intensity. The intensity at which the monkeys maintained the shock 50% of the time (median shock level, MSL) was determined. BW373U86 (1.0-30.0 mg/kg i.m.) increased MSL, but these increases were not dose-dependent and lasted only 15 min or less. Doses of BW373U86 that increased MSL often produced tremors and/or convulsions immediately after administration. When 1.0 mg/kg of naltrindole, a delta opioid antagonist, was given in combination with BW373U86, doses of BW373U86 up to 30 mg/kg no longer increased MSL nor did tremors and/or convulsions occur. Doses of BW373U86 (0.01-0.3 mg/kg i.m.) that did not increase MSL when administered alone shifted the dose-effect curve for the mu agonist l-methadone to the left. These shifts were antagonized dose-dependently by naltrindole. In monkeys that were tolerant to morphine, BW373U86 (0.03-0.1 mg/kg i.m.) shifted the morphine dose-effect curve leftward. In addition, BW373U86 altered the effects of the partial opioid agonists, buprenorphine, nalbuphine, butorphanol and levallorphan such that doses of these drugs that did not increase MSL when administered alone, often did so in the presence of BW373U86. Taken together, these findings indicate that BW373U86 has a delta agonist profile in the squirrel monkey; however, its antinociceptive effects in the shock titration procedure may be due to its toxic effects.