Opioid-induced Loss of Local Anesthetic Potency in the Rat Sciatic Nerve.
Opioid-induced Loss of Local Anesthetic Potency in the Rat Sciatic Nerve.
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DOI：
10.1097/aln.0000000000001239
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发表时间：
2016-10
期刊：
影响因子：
8.8
通讯作者：
Gold MS
中科院分区：
文献类型：
--
作者：
Liu Q;Gold MS
先前的证据表明，阿片类药物耐受患者对局部麻醉剂（LA）用于术后疼痛管理的反应较低。为了确定LA效力的这种明显丧失是否是由于外周神经的内在变化，评估了全身吗啡对离体大鼠坐骨神经中利多卡因诱导的复合动作电位（CAP）阻滞效力的影响。镇痛效果进行了评估与热撤退试验。10 mg/kg吗啡急性给药对利多卡因的效力没有可检测到的影响，每天皮下注射7次吗啡使效力降低3倍（未处理大鼠A波和C波阻滞的EC_（50）分别为186 ± 32μM（n = 6，mean ± SD）和201 ± 31μM（n = 6）;而在每天接受7次吗啡注射（10 mg/kg）的大鼠的神经中分别为608 ± 53μM（n = 6）和613 ± 42 μM（n = 6）（p <0.001））。这种效力的损失是剂量依赖性和注射次数依赖性的，使得利多卡因效力损失的幅度与吗啡耐受性的发展显著（n=6，p < 0.01）相关（r2 = 0.93）。有趣的是，尽管在停止吗啡给药后的几天内镇痛效果完全恢复，但吗啡诱导的利多卡因效力降低甚至在最后一次吗啡注射后35天也完全明显。联合给药纳洛酮（1 mg/kg，i. p.），但不能阻断利多卡因效力的降低。这些临床前数据表明，吗啡诱导的LA效力降低至少部分是由于外周神经的内在变化。确定潜在的机制可能会建议在不断增长的阿片类药物耐受患者人群中更有效的术后疼痛管理策略。
Previous evidence suggests that opioid tolerant patients are less responsive to local anesthetics (LAs) for postoperative pain management. To determine whether this apparent loss of LA potency is due to an intrinsic change in the peripheral nerve, the effect of systemic morphine was assessed on the potency of lidocaine-induced block of the compound action potential (CAP) in isolated rat sciatic nerves. Analgesic efficacy was assessed with the heat withdrawal assay. While acute administration of 10mg/kg morphine had no detectable influence on lidocaine potency, seven daily subcutaneous injections of morphine produced a three-fold decrease in potency (EC50 for block A- and C- waves for naïve rats were 186 ± 32μM (n = 6, mean ± SD) and 201 ± 31μM (n = 6), respectively; versus 608 ± 53μM, (n = 6) and 613 ± 42 μM, (n = 6), respectively (p <0.001), in nerves from rats that had received seven daily injections of morphine (10 mg/kg)). This loss in potency was both dose- and injection number-dependent, such that the magnitude of the loss of lidocaine potency was significantly (n=6, p < 0.01) correlated (r2 = 0.93) with the development of morphine tolerance. Interestingly, despite the complete recovery of analgesic efficacy within days following cessation of morphine administration, the morphine-induced decrease in lidocaine potency was fully manifest even 35 days after the last morphine injection. Co-administration of naloxone (1 mg/kg, i.p.), but not naloxone methiodide (1 mg/kg, s.c) with each of seven daily injections of morphine blocked the decrease in lidocaine potency. These preclinical data suggest that the morphine induced decrease in LA potency is due, at least in part, to the intrinsic changes in the peripheral nerve. Identification of the underlying mechanisms may suggest strategies for more effective post-operative pain management in the growing population of opioid tolerant patients.