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BEHAVIORAL PHARMACOLOGY

Opioid Interactions in Rhesus Monkeys: Effects of + µ and + Agonists on Schedule-Controlled Responding and Thermal Nociception

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

Agonists at , µ, and opioid receptors produce interacting effects in rodents and nonhuman primates. To further evaluate the determinants of these interactions, this study examined the effects of mixtures of + µ and + agonists in rhesus monkeys (n = 4–5) using two behavioral procedures, an assay of schedule-controlled responding for food reinforcement and an assay of thermal nociception. Results were analyzed using dose-addition analysis. In the assay of schedule-controlled responding, the agonist (+)-4-[(R)--((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxy-benzyl]-N,N-diethyl-benzamide (SNC80); the µ agonists methadone, fentanyl, morphine, and nalbuphine; and the agonists (5,7,8)-(–)-N-methyl-N-(7-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl) benzeneacetamide (U69,593) and bremazocine all dose dependently decreased rates of food-maintained responding when administered alone. Fixed ratio mixtures of SNC80 + µ agonists produced additive or subadditive effects, whereas SNC80 + agonist mixtures produced only additive effects. In the assay of thermal nociception, SNC80 produced no measurable effects when administered alone, whereas µ and agonists produced dose-dependent antinociception. SNC80 + µ agonist mixtures produced superadditive effects manifested as leftward shifts in µ agonist dose-effect curves. This synergism was antagonized by the -selective antagonist naltrindole, suggesting that SNC80-induced enhancement of µ agonist antinociception was receptor-mediated. SNC80 did not enhance the antinociceptive effects of the highly selective agonist U69,593, and it produced only a marginal enhancement of antinociception produced by the less selective agonist bremazocine. These results suggest that agonists may selectively enhance the antinociceptive effects of µ agonists in rhesus monkeys. These results also confirm that opioid agonist interactions may depend on the receptor selectivity and relative doses of the agonists and on the experimental endpoint.

Address correspondence to: 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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