TY - JOUR T1 - Opioid Interactions in Rhesus Monkeys: Effects of δ + μ and δ + κ Agonists on Schedule-Controlled Responding and Thermal Nociception JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1054 LP - 1064 DO - 10.1124/jpet.103.056515 VL - 307 IS - 3 AU - Glenn W. Stevenson AU - John E. Folk AU - David C. Linsenmayer AU - Kenner C. Rice AU - S. Stevens Negus Y1 - 2003/12/01 UR - http://jpet.aspetjournals.org/content/307/3/1054.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -