Kandasamy Ram, Lee Andrea T, Morgan Michael M
Graduate Program in Neuroscience, Washington State University, Pullman, WA, USA.
Department of Psychology, Washington State University Vancouver, Vancouver, WA, USA.
Pharmacol Biochem Behav. 2017 May;156:10-15. doi: 10.1016/j.pbb.2017.03.007. Epub 2017 Mar 31.
Opioid withdrawal in humans is often subtle and almost always spontaneous. In contrast, most preclinical studies precipitate withdrawal by administration of an opioid receptor antagonist such as naloxone. These animal studies rely on measurement of physiological symptoms (e.g., wet dog shakes) in the period immediately following naloxone administration. To more closely model the human condition, we tested the hypothesis that depression of home cage wheel running will provide an objective method to measure the magnitude and duration of spontaneous morphine withdrawal. Rats were allowed access to a running wheel in their home cage for 8days prior to implantation of two 75mg morphine or placebo pellets. The pellets were removed 3 or 5days later to induce spontaneous withdrawal. In normal pain-free rats, removal of the morphine pellets depressed wheel running for 48h compared to rats that had placebo pellets removed. Morphine withdrawal-induced depression of wheel running was greatly enhanced in rats with persistent inflammatory pain induced by injection of Complete Freund's Adjuvant (CFA) into the hindpaw. Removal of the morphine pellets following 3days of treatment depressed wheel running in these rats for over 6days. These data demonstrate that home cage wheel running provides an objective and more clinically relevant method to assess spontaneous morphine withdrawal compared to precipitated withdrawal in laboratory rats. Moreover, the enhanced withdrawal in rats with persistent inflammatory pain suggests that pain patients may be especially susceptible to opioid withdrawal.
人类的阿片类药物戒断往往很轻微，而且几乎总是自发的。相比之下，大多数临床前研究通过给予阿片受体拮抗剂（如纳洛酮）来引发戒断反应。这些动物研究依赖于在给予纳洛酮后立即测量生理症状（如湿狗样抖动）。为了更接近地模拟人类情况，我们测试了这样一个假设：家笼中轮子跑动的减少将提供一种客观方法来测量自发吗啡戒断的程度和持续时间。在植入两颗75毫克吗啡或安慰剂药丸之前，让大鼠在家笼中使用轮子跑动8天。3或5天后取出药丸以诱导自发戒断。与取出安慰剂药丸的大鼠相比，在正常无疼痛的大鼠中，取出吗啡药丸会使轮子跑动减少48小时。在通过将完全弗氏佐剂（CFA）注射到后爪诱导出持续性炎症疼痛的大鼠中，吗啡戒断引起的轮子跑动减少大大增强。治疗3天后取出吗啡药丸会使这些大鼠的轮子跑动减少超过6天。这些数据表明，与实验室大鼠中引发的戒断相比，家笼中轮子跑动提供了一种客观且更具临床相关性的方法来评估自发吗啡戒断。此外，持续性炎症疼痛大鼠中增强的戒断表明疼痛患者可能特别容易出现阿片类药物戒断。
