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BEHAVIORAL PHARMACOLOGY

Interactions between and µ Opioid Agonists in Assays of Schedule-Controlled Responding, Thermal Nociception, Drug Self-Administration, and Drug versus Food Choice in Rhesus Monkeys: Studies with SNC80 [(+)-4-[(R)--((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide] and Heroin

Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, Belmont, Massachusetts (G.W.S., S.S.N.); and Laboratory of Medicinal Chemistry, National Institute on Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (J.E.F., K.C.R.)

Interactions between and µ opioid agonists in rhesus monkeys vary as a function of the behavioral endpoint. The present study compared interactions between the agonist SNC80 [(+)-4-[(R)--((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide] and the µ agonist heroin in assays of schedule-controlled responding, thermal nociception, and drug self-administration. Both SNC80 (ED₅₀ = 0.43 mg/kg) and heroin (ED₅₀ = 0.088 mg/kg) produced a dose-dependent and complete suppression of response rates in the assay of schedule-controlled responding. Heroin also produced thermal antinociception (ED_5°C = 0.18 mg/kg) and maintained drug self-administration under both a fixed ratio schedule [dose-effect curve peak at 0.0032 mg/kg/injection (inj)] and under a food versus heroin concurrent-choice schedule (ED₅₀ = 0.013 mg/kg/inj), whereas SNC80 did not produce thermal antinociception or maintain self-administration. Fixed ratio mixtures of SNC80 and heroin (1.6:1, 4.7:1, and 14:1 SNC80/heroin) produced additive effects in the assay of schedule-controlled responding and superadditive effects in the assay of thermal nociception. Also, SNC80 did not enhance the reinforcing effects of heroin, indicating that mixtures of SNC80 and heroin produced additive or infra-additive reinforcing effects. These results provide additional evidence to suggest that /µ interactions depend on the experimental endpoint and further suggest that agonists may selectively enhance the antinociceptive effects of µ agonists while either not affecting or decreasing the sedative and reinforcing effects of µ agonists.

Address correspondence to: Dr. S. Stevens Negus, Alcohol and Drug Abuse Research Center, Harvard Medical School, McLean Hospital, 115 Mill St., Belmont, MA 02478-9106. E-mail: negus{at}mclean.harvard.edu

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