Opioid Interactions in Rhesus Monkeys: Effects of δ + μ and δ + κ 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.)
- 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
Abstract
Agonists at δ, μ, and κ 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 δ + μ and δ + κ 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 δ agonist (+)-4-[(αR)-α-((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 κ agonists (5α,7α,8β)-(–)-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 + κ agonist mixtures produced only additive effects. In the assay of thermal nociception, SNC80 produced no measurable effects when administered alone, whereas μ and κ 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 δ-selective antagonist naltrindole, suggesting that SNC80-induced enhancement of μ agonist antinociception was δ receptor-mediated. SNC80 did not enhance the antinociceptive effects of the highly selective κ agonist U69,593, and it produced only a marginal enhancement of antinociception produced by the less selective κ agonist bremazocine. These results suggest that δ 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.
Footnotes
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This work was supported by Grants R01-DA11460, T32-DA07252, and P01-DA14528 from the National Institute on Drug Abuse, National Institutes of Health.
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DOI: 10.1124/jpet.103.056515.
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ABBREVIATIONS: DPDPE, [d-Pen2,d-Pen5]-enkephalin; SNC80, (+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxy-benzyl]-N,N-diethyl-benzamide; BW373U86, (±)-4-[(R*)-[(2S*,5R*)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide hydrochloride; PL017, [N-MePhe3,d-Pro4]morphiceptin.
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- Received July 3, 2003.
- Accepted August 29, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
