Effects of Atypical κ-Opioid Receptor Agonists on Intrathecal Morphine-Induced Itch and Analgesia in Primates
Effects of Atypical κ-Opioid Receptor Agonists on Intrathecal Morphine-Induced Itch and Analgesia in Primates
复制标题
DOI：
10.1124/jpet.108.143925
复制
发表时间：
2009-01-01
影响因子：
3.5
通讯作者：
Husbands, Stephen M.
中科院分区：
文献类型：
--
作者：
Ko, Mei-Chuan;Husbands, Stephen M.
瘙痒/瘙痒症是与给予人类用于镇痛的吗啡脊髓给药相关的最常见副作用。本研究的目的是研究具有不同化学结构的κ-阿片受体（KOR）激动剂作为止痒剂的有效性，并阐明猴止痒作用的受体机制。特别地，先前提出的非KOR-1激动剂，包括纳呋拉芬{TRK-820，17-环丙基甲基-3，14 β-二羟基-4，5 α-环氧基-6 β-{N-甲基-反式-3-（3-呋喃基）丙烯酰胺基]吗啡喃]、布雷佐辛[（+/-）-6-乙基-1，2，3，4，5，6-六氢-3-[（+/-）-1，2，3，4，（1-羟基环丙基）甲基]-11，11-二甲基-2，6-亚甲基-3-苯并氮杂环辛-8-醇]和GR 89696 {4-[（3，4-二氯苯基）乙酰基]-3-（1-吡咯烷基甲基）-1-哌嗪羧酸甲酯]在各种行为测定中进行了研究，用于测量瘙痒/抓挠，镇痛，和呼吸抑制。全身给予纳呋拉芬（0.1-1 μ g/kg）、布马佐辛（0.1-1 μ g/kg）或GR 89696（0.01-0.1 μ g/kg）剂量依赖性地减弱鞘内吗啡（0.03 mg）诱导的抓挠反应，而不影响吗啡抗伤害感受。鞘内吗啡与这些KOR激动剂的组合不引起镇静。此外，预先给予有效抗抓挠剂量的纳呋萘芬、布马佐辛或GR 89696，并不能拮抗全身吗啡诱导的抗伤害感受和呼吸抑制。剂量加和分析显示纳呋拉芬与吗啡联合用药的抗伤害效应无次加和性。此外，KOR拮抗剂研究表明，纳呋拉芬和原型KOR-1激动剂U-50488 H（反式-（+/-）-3，4-二氯-N-甲基-N-（2-{1-吡咯烷基]环己基）-苯乙酰胺）的抗抓挠作用可被选择性KOR拮抗剂nor-binaltorphimine（3 mg/kg）完全阻断。这些结果表明，对KOR的激动剂作用主要有助于这些非典型KOR激动剂作为止痒剂的有效性，并且没有证据表明KOR亚型或μ阿片拮抗剂作用是这些KOR激动剂作用的基础。这项基于机制的研究进一步支持了KOR激动剂在脊髓阿片类镇痛背景下作为止痒剂的临床潜力。
Itch/pruritus is the most common side effect associated with spinal administration of morphine given to humans for analgesia. The aim of this study was to investigate the effectiveness of kappa-opioid receptor (KOR) agonists with diverse chemical structures as antipruritics and to elucidate the receptor mechanism underlying the antipruritic effect in monkeys. In particular, previously proposed non-KOR-1 agonists, including nalfurafine {TRK-820, 17-cyclopropylmethyl-3,14 beta-dihydroxy-4,5 alpha-epoxy-6 beta -{N-methyl-trans-3-(3-furyl)acrylamido]morphinan], bremazocine [(+/-)- 6-ethyl- 1,2,3,4,5,6-hexahydro-3-[(1-hydroxycyclopropy)methyl]-11,11-dimethyl-2,6-methano-3-benzazocin-8-ol], and GR 89696 {4-[(3,4-dichlorophenyl) acetyl]-3-(1-pyrrolidinylmethyl)-1piperazinecarboxylic acid methyl ester] were studied in various behavioral assays for measuring itch/scratching,analgesia, and respiratory depression. Systemic administration of nalfurafine (0.1-1 mu g/kg), bremazocine (0.1-1 mu g/kg), or GR 89696 (0.01-0.1 mu g/kg) dose-dependently attenuated intrathecal morphine (0.03 mg)-induced scratching responses without affecting morphine antinociception. The combination of intrathecal morphine with these KOR agonists did not cause sedation. In addition, pretreatment with effective antiscratching doses of nalfurafine, bremazocine, or GR 89696 did not antagonize systemic morphine-induced antinociception and respiratory depression. The dose-addition analysis revealed that there is no subadditivity for nalfurafine in combination with morphine in the antinociceptive effect. Furthermore, the KOR antagonist study revealed that antiscratching effects of both nalfurafine and a prototypical KOR-1 agonist, U-50488H {trans-(+/-)- 3,4-dichloro-N-methyl-N-(2-{1-pyrrolidinyl]cyclohexyl)- benzeneacetamide], could be blocked completely by a selective KOR antagonist, nor-binaltorphimine (3 mg/kg). These findings suggest that the agonist action on KOR mainly contributes to the effectiveness of these atypical KOR agonists as antipruritics, and there is no evidence for KOR subtypes or mu-opioid antagonist action underlying the effects of these KOR agonists. This mechanism-based study further supports the clinical potential of KOR agonists as antipruritics under the context of spinal opioid analgesia.