Peripherally acting mu-opioid receptor agonist attenuates neuropathic pain in rats after L5 spinal nerve injury
Peripherally acting mu-opioid receptor agonist attenuates neuropathic pain in rats after L5 spinal nerve injury
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DOI：
10.1016/j.pain.2008.01.004
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发表时间：
2008-08-31
期刊：
影响因子：
7.4
通讯作者：
Raja, Srinivasa N.
中科院分区：
文献类型：
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作者：
Guan, Yun;Johanek, Lisa M.;Raja, Srinivasa N.
实验模型和对照患者试验的研究表明，阿片类药物在控制神经病理性疼痛方面有效。然而，它们继发于中枢神经系统的副作用阻碍了它们的临床应用。因此。我们观察了L5脊神经结扎(SNL)后激活外周阿片受体(MORS)是否能有效减轻神经病理性疼痛。全身性盐酸洛哌丁胺(0.3-10 mg/kg，S.C.)。作为一种外周作用的偏爱MOR的激动剂，在SNL后第7天剂量依赖性地逆转了机械性痛觉异常。全身用氯哌丁胺(1.5 mg/kg)可产生抗痛觉异常的作用。S.C.)可被盐酸纳洛酮(10 mg/kg)系统预处理所阻断。I.P.)或甲基纳曲松(5 mg/kg，i.p)，一种外周作用的、偏爱MOR的拮抗剂。用甲基纳曲酮(43.5mU g/50亩L)和高选择性吗啡拮抗剂CTAP(5.5mU g/50亩L)对其进行同侧足底注射阻断。然而。阿片受体拮抗剂盐酸那曲吲哚(45.1mg50亩L)足底注射不能阻断洛哌丁胺的这种抗痛觉超敏作用，其抗痛觉超敏作用随时间变化，在SNL后7、28、42d的作用相似，但在SNL后14d作用减弱。在SNL后第7天，同侧足底注射洛哌丁胺(10-100微克/50微克)也可剂量依赖性地逆转机械性超敏反应。我们认为洛哌丁胺能有效地减轻神经病理性疼痛。主要通过激活局部组织中的外周MORS。因此。外周作用的MOR激动剂可能是缓解神经病理性疼痛的一种有前途的治疗方法。(C)2005年国际疼痛研究协会。爱思唯尔出版，版权所有。
Studies in experimental models and controlled patient trials indicate that opioids are effective in managing neuropathic pain. However, side effects secondary to their central nervous system actions present barriers to their clinical use. Therefore. we examined whether activation of the periphetal mu-opioid receptors (MORs) could effectively alleviate neuropathic pain ill rats after L5 spinal nerve ligation (SNL). Systemic loperamide hydrochloride (0.3-10 mg/kg, s.c.). a peripherally acting MOR-preferring agonist, dose-dependently reversed the mechanical allodynia at day 7 post-SNL. This anti-allodynic effect produced by systemic loperamide (1.5 mg/kg. s.c.) was blocked by systemic pretreatment with either naloxone hydrochloride ( 10 mg/kg. i.p.) or methyl-naltresone (5 mg/kg, i.p.), a peripherally acting, MOR-preferring antagonist. It was also blocked by ipsilateral intraplantar pretreatment with methyl-naltrexone (43.5 mu g/50 mu l) and the highly selective MOR antagonist CTAP (5.5 mu g/50 mu l). However. this anti-allodynic effect of systemic loperamide was not blocked by intraplantar pretreatment with the delta-opioid receptor antagonist naltrindole hydrochloride (45.1 mu g/50 mu l), The anti-allodynic potency of systemic loperamide varied with time after nerve injury, with similar potency tit days 7, 28, and 42 post-SNL, but reduced potency at day 14 post-SNL. Ipsilateral intraplantar injection of loperamide also dose-dependently (10-100 mu g/50 mu g) reversed mechanical allodynia on day 7 post-SNL. We suggest that loperamide can effectively attenuate neuropathic pain. primarily through activation of peripheral MORs in local tissue. Therefore. peripherally acting MOR agonists may represent a promising therapeutic approach for alleviating neuropathic pain. (C) 2005 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.