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 antinoc iceptive effects of the novel delta opioid agonist iperazinyl)-3-hydro xy-benzyl)-N,N-diethylbenzamide (BW373U86). Under this procedure shock increased every 15 sec from 0.01 to 2.0 mA in 30 steps. Five response s terminated the shock for 15 sec, after which the shock resumed at a lower intensity. The intensity at which the monkeys maintained the sho ck 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 incr eased MSL often produced tremors and/or convulsions immediately after administration. When 1.0 mg/kg of naltrindole, a delta opioid antagoni st, was given in combination with BW373U86, doses of BW373U86 up to 30 mg/kg no longer increased MSL nor did tremors and/or convulsions occu r. Doses of BW373U86 (0.01-0.3 mg/kg i.m.) that did not increase MSL w hen administered alone shifted the dose-effect curve for the mu agonis t I-methadone to the left. These shifts were antagonized dose-dependen tly by naltrindole. In monkeys that were tolerant to morphine, BW373U8 6 (0.03-0.1 mg/kg i.m.) shifted the morphine dose-effect curve leftwar d. In addition, BW373U86 altered the effects of the partial opioid ago nists, buprenorphine, nalbuphine, butorphanol and levallorphan such th at doses of these drugs that did not increase MSL when administered al one, often did so in the presence of BW373U86. Taken together, these f indings indicate that BW373U86 has a delta agonist profile in the squi rrel monkey; however, its antinociceptive effects in the shock titrati on procedure may be due to its toxic effects.