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Vol. 286, Issue 1, 362-375, July 1998

Behavioral Effects of the Delta-Selective Opioid Agonist SNC80 and Related Compounds in Rhesus Monkeys1

S. Stevens Negus, Michael B. Gatch, Nancy K. Mello, Xiaoyan Zhang and Kenner Rice

Alcohol and Drug Abuse Research Center, Harvard Medical School, McLean Hospital, Belmont, Massachusetts (S.S.N., M.B.G., N.K.M.); and Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (X.Z., K.R.)

The behavioral effects of the nonpeptidic delta opioid agonist SNC80 and a series of related piperazinyl benzamides derived from the parent compound BW373U86 were evaluated in rhesus monkeys. SNC80 (0.1-10 mg/kg) decreased response rates maintained by food-reinforcement in a dose- and time-dependent manner, with maximal effects occuring within 10 min of intramuscular injection. The potency of SNC80 and five other piperazinyl benzamides in this assay of schedule-controlled responding correlated with their affinity at cloned human delta opioid receptors but not with their affinity for cloned human mu receptors. Moreover, the effects of SNC80 were selectively antagonized by the delta-selective antagonist naltrindole (1.0 mg/kg), but not by the mu selective antagonist quadazocine (0.1 mg/kg) or the kappa-selective antagonist nor-binaltorphimine (3.2 mg/kg). These findings indicate that SNC80 functions as a systemically active, delta-selective agonist with a rapid onset of action in rhesus monkeys. The antinociceptive effects of SNC80 were examined in a warm-water tail-withdrawal assay of thermal nociception. SNC80 (0.1-10 mg/kg) produced weak but replicable antinociceptive effects that were antagonized by naltrindole (1.0 mg/kg). SNC80 antinociception was also dose-dependently antagonized by BW373U86 (0.56-1.0 mg/kg), which was inactive in this procedure. These findings suggest that SNC80 may have higher efficacy than BW373U86 at delta opioid receptors. Moreover, SNC80 at doses up to 32 mg/kg did not produce convulsions, which suggests that SNC80 may also be safer than BW373U86. The effects of SNC80 were also examined in monkeys trained to discriminate cocaine (0.4 mg/kg i.m.) or self-administer cocaine (0.032 mg/kg/injection,i.v.). In drug discrimination studies, SNC80 (0.1-10 mg/kg) produced a dose-dependent and naltrindole-reversible increase in cocaine-appropriate responding, and complete substitution for cocaine was observed in five of seven monkeys tested. However, SNC80 (1.0-100 µg/kg/injection) did not maintain responding in monkeys trained to self-administer cocaine. Thus, despite its ability to produce cocaine-like discriminative stimulus effects, SNC80 may have relatively low abuse potential.

0022-3565/98/2861-0362$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


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