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.