Ross Fraser B, Smith Maree T
School of Pharmacy, Steele Building, The University of Queensland, St. Lucia, Brisbane, Queensland 4072, Australia.
Pain. 1997 Nov;73(2):151-157. doi: 10.1016/S0304-3959(97)00093-6.
Our previous studies in the Sprague-Dawley rat showed that the intrinsic antinociceptive effects of oxycodone are naloxone reversible in a manner analogous to morphine but that in contrast to morphine, oxycodone's antinociceptive effects have a rapid onset of maximum effect (approximately 5-7 min compared to 30-45 min for morphine), comprise one antinociceptive phase (compared to two phases) and are of relatively short duration (approximately 90 min compared to approximately 180 min). In the present study, administration of a range of selective opioid receptor antagonists has shown that the intrinsic antinociceptive effects of oxycodone (171 nmol) are not attenuated by i.c.v. administration of (i) naloxonazine, a mu1-selective opioid receptor antagonist, or (ii) naltrindole, a delta-selective opioid receptor antagonist, in doses that completely attenuated the intrinsic antinociceptive effects of equipotent doses of the respective mu- and delta-opioid agonists, morphine and enkephalin-[D-Pen(2,5)] (DPDPE). Although beta-funaltrexamine (beta-FNA) attenuated the antinociceptive effects of oxycodone (171 nmol i.c.v.), it also attenuated the antinociceptive effects of morphine and bremazocine (kappa-opioid agonist) indicative of non-selective antagonism. Importantly, the antinociceptive effects of oxycodone (171 nmol i.c.v.) were markedly attenuated by the prior i.c.v. administration of the selective kappa-opioid receptor antagonist, norbinaltorphimine (nor-BNI), in a dose (0.3 nmol) that did not attenuate the antinociceptive effects of an equipotent dose of i.c.v. morphine (78 nmol). Taken together, these data strongly suggest that the intrinsic antinociceptive effects of oxycodone are mediated by kappa-opioid receptors, in contrast to morphine which interacts primarily with mu-opioid receptors.
我们之前在斯普拉格-道利大鼠上的研究表明，羟考酮的内在抗伤害感受作用与吗啡类似，可被纳洛酮逆转，但与吗啡不同的是，羟考酮的抗伤害感受作用起效迅速，达到最大效应的时间较短（约5 - 7分钟，而吗啡为30 - 45分钟），包含一个抗伤害感受阶段（吗啡为两个阶段），且持续时间相对较短（约90分钟，吗啡约为180分钟）。在本研究中，给予一系列选择性阿片受体拮抗剂后发现，羟考酮（171纳摩尔）的内在抗伤害感受作用不会因脑室内注射以下物质而减弱：（i）纳洛嗪，一种μ1选择性阿片受体拮抗剂；或（ii）纳曲吲哚，一种δ选择性阿片受体拮抗剂，这两种拮抗剂的剂量能完全减弱等剂量的相应μ和δ阿片激动剂吗啡和脑啡肽 - [D - Pen(2,5)]（DPDPE）的内在抗伤害感受作用。尽管β - 氟纳曲明（β - FNA）减弱了羟考酮（脑室内注射171纳摩尔）的抗伤害感受作用，但它也减弱了吗啡和布马佐辛（κ阿片激动剂）的抗伤害感受作用，表明其具有非选择性拮抗作用。重要的是，脑室内预先注射选择性κ阿片受体拮抗剂诺宾那托啡（nor - BNI）（剂量为0.3纳摩尔）可显著减弱羟考酮（脑室内注射171纳摩尔）的抗伤害感受作用，而该剂量不会减弱等剂量脑室内注射吗啡（78纳摩尔）的抗伤害感受作用。综上所述，这些数据强烈表明，羟考酮的内在抗伤害感受作用是由κ阿片受体介导的，这与主要与μ阿片受体相互作用的吗啡不同。
