The role of central μ opioid receptors in opioid-induced itch in primates
The role of central μ opioid receptors in opioid-induced itch in primates
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DOI：
10.1124/jpet.103.061101
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发表时间：
2004-07-01
影响因子：
3.5
通讯作者：
Naughton, NN
中科院分区：
文献类型：
--
作者：
Ko, MCH;Song, MS;Naughton, NN
瘙痒（痒感）是一个重要的临床问题。本研究的目的是阐明阿片受体类型和作用部位在阿片诱导的猴瘙痒中的作用。对条件不知情的观察者在给予各种药物后计数抓挠。静脉注射（i. v.）μ阿片受体（莫尔）激动剂（芬太尼、阿芬太尼、雷米芬太尼和吗啡）的给药以剂量和时间依赖性方式诱发抓挠。然而，κ阿片激动剂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]和δ阿片激动剂SNC 80 [（+）-4-[（alphaR）-α-[2S，5 R）-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]不增加抓挠。鞘内（i.t.）给予肽类莫尔受体激动剂[D-Ala（2），N-Me-Phe（4），Gly（5）-ol]-脑啡肽（DAMGO，0.00032-0.01 mg）诱发抓挠，但静脉注射DAMGO（0.01-1 mg/kg）不增加抓挠。类似的区别在i.t.静脉注射吗啡也有效。拮抗剂研究表明，静脉注射阿片受体拮抗剂（纳洛酮，0.0032-0.1 mg/kg）剂量依赖性地减弱静脉注射芬太尼（0.018 mg/kg）或吗啡（1 mg/kg）诱导的抓挠。然而，外周选择性阿片类拮抗剂（季纳洛酮，0.0032-0.32 mg/kg）不能阻断静脉注射芬太尼或吗啡诱导的抓挠。此外，组胺拮抗剂（苯海拉明，0.1-10 mg/kg）不能减轻i.t.吗啡（0.032 mg）或静脉注射吗啡（1 mg/kg）。用选择性莫尔拮抗剂（clocinnamox，0.1 mg/ kg）预处理，而不是κ或δ阿片拮抗剂（nor-binaltorphimine或naltrindole），阻断i.t.吗啡引起的抓挠总之，这些数据表明，莫尔，而不是其他阿片受体类型或组胺，介导阿片类镇痛药引起的抓挠。更重要的是，这项研究提供了体内药理学证据，表明中枢莫尔的激活在阿片类药物诱导的灵长类动物瘙痒中起重要作用。
Pruritus ( itch sensation) is a significant clinical problem. The aim of this study was to elucidate the roles of opioid receptor types and the site of action in opioid-induced itch in monkeys. Observers who were blinded to the conditions counted scratching after administration of various drugs. Intravenous (i.v.) administration of mu opioid receptor (MOR) agonists (fentanyl, alfentanil, remifentanil, and morphine) evoked scratching in a dose- and time-dependent manner. However, the kappa opioid agonist U-50488H [trans-(+/-)-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]-cyclohexyl)-benzeneacetamide] and delta opioid agonist SNC80 [(+)-4-[(alphaR)-alpha-[2S, 5R)-4-allyl-2,5-dimethyl-1- piperazinyl]-3-methoxybenzyl]-N, N-diethylbenzamide] did not increase scratching. Intrathecal (i.t.) administration of peptidic MOR agonist [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin (DAMGO, 0.00032-0.01 mg) evoked scratching, but i.v. DAMGO (0.01-1 mg/kg) did not increase scratching. A similar difference between i.t. and i.v. effectiveness was seen with morphine. Antagonist studies revealed that i.v. administration of an opioid receptor antagonist (naltrexone, 0.0032-0.1 mg/kg) dose dependently attenuated scratching induced by i.v. fentanyl (0.018 mg/kg) or morphine (1 mg/kg). However, a peripherally selective opioid antagonist (quaternary naltrexone, 0.0032-0.32 mg/kg) did not block i.v. fentanyl- or morphine-induced scratching. Moreover, a histamine antagonist (diphenhydramine, 0.1-10 mg/kg), failed to attenuate scratching induced by i.t. morphine (0.032 mg) or i.v. morphine (1 mg/kg). Pretreatment with a selective MOR antagonist (clocinnamox, 0.1 mg/ kg), but not kappa or delta opioid antagonists (nor-binaltorphimine or naltrindole), blocked i.t. morphine-induced scratching. Together, these data suggest that MOR, not other opioid receptor types or histamine, mediates scratching evoked by opioid analgesics. More important, this study provides in vivo pharmacological evidence that activation of central MOR plays an important role in opioid-induced itch in primates.