外周作用阿片类药物洛哌丁胺盐酸盐在神经损伤大鼠中产生抗痛觉过敏作用的耐受性。
Tolerance develops to the antiallodynic effects of the peripherally acting opioid loperamide hydrochloride in nerve-injured rats.
机构信息
Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University, School of Medicine, Baltimore, MD, USA Department of Pharmacology, Physiology and Neuroscience, University of South Carolina, Columbia, SC, USA Department of Clinical Pharmacology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, China Department of Anesthesiology and Pain Medicine, School of Medicine, Wonkwang University, Ikscan, South Korea Department of Neuroscience, The Johns Hopkins University, School of Medicine, Baltimore, MD, USA.
出版信息
Pain. 2013 Nov;154(11):2477-2486. doi: 10.1016/j.pain.2013.07.023. Epub 2013 Jul 20.
Peripherally acting opioids are potentially attractive drugs for the clinical management of certain chronic pain states due to the lack of centrally mediated adverse effects. However, it remains unclear whether tolerance develops to peripheral opioid analgesic effects under neuropathic pain conditions. We subjected rats to L5 spinal nerve ligation (SNL) and examined the analgesic effects of repetitive systemic and local administration of loperamide hydrochloride, a peripherally acting opioid agonist. We found that the inhibition of mechanical hypersensitivity, an important manifestation of neuropathic pain, by systemic loperamide (1.5mg/kg subcutaneously) decreased after repetitive drug treatment (tolerance-inducing dose: 0.75 to 6.0mg/kg subcutaneously). Similarly, repeated intraplantar injection of loperamide (150 μg/50 μL intraplantarly) and D-Ala(2)-MePhe(4)-Glyol(5) enkephalin (300 μg/50 μL), a highly selective mu-opioid receptor (MOR) agonist, also resulted in decreased inhibition of mechanical hypersensitivity. Pretreatment with naltrexone hydrochloride (5mg/kg intraperitoneally) and MK-801 (0.2mg/kg intraperitoneally) attenuated systemic loperamide tolerance. Western blot analysis showed that repetitive systemic administration of morphine (3mg/kg subcutaneously), but not loperamide (3mg/kg subcutaneously) or saline, significantly increased MOR phosphorylation in the spinal cord of SNL rats. In cultured rat dorsal root ganglion neurons, loperamide dose-dependently inhibited KCl-induced increases in [Ca(2+)]i. However, this drug effect significantly decreased in cells pretreated with loperamide (3 μM, 72 hours). Intriguingly, in loperamide-tolerant cells, the delta-opioid receptor antagonist naltrindole restored loperamide's inhibition of KCl-elicited [Ca(2+)]i increase. Our findings indicate that animals with neuropathic pain may develop acute tolerance to the antiallodynic effects of peripherally acting opioids after repetitive systemic and local drug administration.
周围作用阿片类药物由于缺乏中枢介导的不良反应，对于某些慢性疼痛状态的临床治疗具有潜在吸引力。然而，在外周阿片类药物镇痛作用下是否会产生神经病理性疼痛条件下的耐受仍然不清楚。我们使大鼠遭受 L5 脊神经结扎（SNL），并检查了重复全身和局部给予盐酸洛哌丁胺（一种外周作用阿片激动剂）的镇痛作用。我们发现，全身洛哌丁胺（皮下 1.5mg/kg）对机械性超敏反应的抑制作用（神经病理性疼痛的一个重要表现）在重复药物治疗后降低（诱导耐受剂量：皮下 0.75 至 6.0mg/kg）。同样，重复足底内注射洛哌丁胺（150μg/50μL 足底内）和 D-Ala(2)-MePhe(4)-Glyol(5) 脑啡肽（300μg/50μL），一种高度选择性的 mu-阿片受体（MOR）激动剂，也导致机械性超敏反应抑制作用降低。盐酸纳洛酮（5mg/kg 腹腔内）和 MK-801（0.2mg/kg 腹腔内）预处理减弱了全身洛哌丁胺的耐受。Western blot 分析表明，重复皮下给予吗啡（3mg/kg），而不是洛哌丁胺（3mg/kg）或生理盐水，显著增加了 SNL 大鼠脊髓中 MOR 的磷酸化。在培养的大鼠背根神经节神经元中，洛哌丁胺剂量依赖性地抑制 KCl 诱导的[Ca(2+)]i 增加。然而，在预先用洛哌丁胺（3μM，72 小时）处理的细胞中，这种药物作用显著降低。有趣的是，在洛哌丁胺耐受细胞中，delta-阿片受体拮抗剂纳曲吲哚恢复了洛哌丁胺对 KCl 诱导的[Ca(2+)]i 增加的抑制作用。我们的研究结果表明，患有神经病理性疼痛的动物在重复全身和局部药物给药后可能会对周围作用阿片类药物的抗痛觉过敏作用产生急性耐受。
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