阿片类药物导致大鼠坐骨神经局部麻醉效能丧失
Opioid-induced Loss of Local Anesthetic Potency in the Rat Sciatic Nerve.
作者信息
Liu Qing, Gold Michael S
机构信息
From the Department of Anesthesiology (Q.L., M.S.G.), Division of Gastroenterology Hepatology and Nutrition, Department of Medicine (M.S.G.), and Department of Neurobiology (M.S.G.), University of Pittsburgh, Pittsburgh, Pennsylvania.
出版信息
Anesthesiology. 2016 Oct;125(4):755-64. doi: 10.1097/ALN.0000000000001239.
BACKGROUND
Previous evidence suggests that opioid-tolerant patients are less responsive to local anesthetics (LAs) for postoperative pain management.
METHODS
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 in isolated rat sciatic nerves. Analgesic efficacy was assessed with the heat withdrawal assay.
RESULTS
While acute administration of 10 mg/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 naive rats were [mean ± SD] 186 ± 32 μM [n = 6] and 201 ± 31 μM [n = 6], respectively, vs. 608 ± 53 μM [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-dependent and injection number dependent, such that the magnitude of the loss of lidocaine potency was significantly (n = 6; P < 0.01) correlated (r = 0.93) with the development of morphine tolerance. Interestingly, despite the complete recovery of analgesic efficacy within days after cessation of morphine administration, the morphine-induced decrease in lidocaine potency was fully manifest even 35 days after the last morphine injection. Coadministration of naloxone (1 mg/kg, intraperitoneally), but not of naloxone methiodide (1 mg/kg, subcutaneously), with each of seven daily injections of morphine blocked the decrease in lidocaine potency.
CONCLUSIONS
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 postoperative pain management in the growing population of opioid-tolerant patients.
背景
先前的证据表明，阿片类药物耐受的患者对用于术后疼痛管理的局部麻醉药（LA）反应较差。
方法
为了确定LA效力的这种明显丧失是否是由于周围神经的内在变化所致，评估了全身应用吗啡对利多卡因诱导的离体大鼠坐骨神经复合动作电位阻滞效力的影响。用热撤离试验评估镇痛效果。
结果
虽然急性给予10mg/kg吗啡对利多卡因效力没有可检测到的影响，但每日皮下注射吗啡7天会使效力降低三倍（未用吗啡处理的大鼠中，A波和C波阻滞的EC50[均值±标准差]分别为186±32μM[n = 6]和201±31μM[n = 6]，而在接受每日注射吗啡（10mg/kg）7天的大鼠的神经中，分别为608±53μM[n = 6]和613±42μM[n = 6][P < 0.001]）。这种效力丧失是剂量依赖性和注射次数依赖性的，以至于利多卡因效力丧失的程度与吗啡耐受性的发展显著相关（n = 6；P < 0.01）（r = 0.93）。有趣的是，尽管在停止给予吗啡后数天内镇痛效果完全恢复，但即使在最后一次注射吗啡后35天，吗啡诱导的利多卡因效力降低仍完全显现。在每日7次注射吗啡时，同时腹腔注射纳洛酮（1mg/kg），而非皮下注射甲基碘化纳洛酮（1mg/kg），可阻止利多卡因效力的降低。
结论
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周围神经的内在变化所致。确定潜在机制可能会为在不断增加的阿片类药物耐受患者群体中更有效地进行术后疼痛管理提供策略。
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