Stevenson Glenn W, Folk John E, Linsenmayer David C, Rice Kenner C, Negus S Stevens
Alcohol and Drug Abuse Research Center, Harvard Medical School, McLean Hospital, 115 Mill St., Belmont, MA 02478-9106, USA.
J Pharmacol Exp Ther. 2003 Dec;307(3):1054-64. doi: 10.1124/jpet.103.056515. Epub 2003 Oct 13.
Agonists at delta, mu, and kappa 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 delta + mu and delta + kappa 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 delta agonist (+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxy-benzyl]-N,N-diethyl-benzamide (SNC80); the mu agonists methadone, fentanyl, morphine, and nalbuphine; and the kappa agonists (5alpha,7alpha,8beta)-(-)-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 + mu agonists produced additive or subadditive effects, whereas SNC80 + kappa agonist mixtures produced only additive effects. In the assay of thermal nociception, SNC80 produced no measurable effects when administered alone, whereas mu and kappa agonists produced dose-dependent antinociception. SNC80 + mu agonist mixtures produced superadditive effects manifested as leftward shifts in mu agonist dose-effect curves. This synergism was antagonized by the delta-selective antagonist naltrindole, suggesting that SNC80-induced enhancement of mu agonist antinociception was delta receptor-mediated. SNC80 did not enhance the antinociceptive effects of the highly selective kappa agonist U69,593, and it produced only a marginal enhancement of antinociception produced by the less selective kappa agonist bremazocine. These results suggest that delta agonists may selectively enhance the antinociceptive effects of mu 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.
δ、μ和κ阿片受体激动剂在啮齿动物和非人类灵长类动物中会产生相互作用。为了进一步评估这些相互作用的决定因素，本研究使用两种行为程序，即对食物强化的程序控制反应测定法和热伤害感受测定法，研究了δ + μ和δ + κ激动剂混合物对恒河猴（n = 4 - 5）的影响。使用剂量相加分析对结果进行分析。在程序控制反应测定中，δ激动剂(+)-4-[(αR)-α-((2S,5R)-4-烯丙基-2,5-二甲基-1-哌嗪基)-3-甲氧基苄基]-N,N-二乙基苯甲酰胺（SNC80）；μ激动剂美沙酮、芬太尼、吗啡和纳布啡；以及κ激动剂(5α,7α,8β)-(-)-N-甲基-N-(7-(1-吡咯烷基)-1-氧杂螺(4,5)癸-8-基)苯乙酰胺（U69,593）和布马佐辛单独给药时均剂量依赖性地降低了食物维持反应的速率。SNC80与μ激动剂的固定比例混合物产生相加或亚相加效应，而SNC80与κ激动剂的混合物仅产生相加效应。在热伤害感受测定中，单独给予SNC80时未产生可测量的效应，而μ和κ激动剂产生剂量依赖性的抗伤害感受作用。SNC80与μ激动剂的混合物产生超相加效应，表现为μ激动剂剂量-效应曲线向左移动。这种协同作用被δ选择性拮抗剂纳曲吲哚拮抗，表明SNC80诱导的μ激动剂抗伤害感受增强是由δ受体介导的。SNC80没有增强高选择性κ激动剂U69,593的抗伤害感受作用，并且它仅使选择性较低的κ激动剂布马佐辛产生的抗伤害感受有轻微增强。这些结果表明，δ激动剂可能在恒河猴中选择性地增强μ激动剂的抗伤害感受作用。这些结果还证实，阿片受体激动剂的相互作用可能取决于激动剂的受体选择性、相对剂量以及实验终点。
