Depression of home cage wheel running is an objective measure of spontaneous morphine withdrawal in rats with and without persistent pain
Depression of home cage wheel running is an objective measure of spontaneous morphine withdrawal in rats with and without persistent pain
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DOI：
10.1016/j.pbb.2017.03.007
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发表时间：
2017-05-01
影响因子：
3.6
通讯作者：
Morgan, Michael M.
中科院分区：
文献类型：
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作者：
Kandasamy, Ram;Lee, Andrea T.;Morgan, Michael M.
人类的阿片类药物戒断通常是微妙的，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加速戒断。这些动物研究依赖于在服用纳洛酮后的一段时间内对生理症状(如湿狗抖动)的测量。为了更好地模拟人类的情况，我们测试了这样一种假设，即家庭笼子车轮跑的抑郁将提供一种客观的方法来衡量自发吗啡戒断的程度和持续时间。在两个75毫克的吗啡或安慰剂药丸植入之前，大鼠被允许在家中的笼子里使用跑轮8天。3或5天后取出微丸以诱导自发戒断。在正常无痛大鼠中，与去除安慰剂颗粒的大鼠相比，去除吗啡颗粒的大鼠车轮运行时间减少了48小时。在足后掌注射完全弗氏佐剂(CFA)所致的持续性炎性痛大鼠中，吗啡戒断所致的车轮跑抑制作用明显增强。治疗3天后摘除吗啡颗粒，使这些大鼠的转轮运动抑制6天以上。这些数据表明，与催促戒断相比，家庭笼轮跑提供了一种客观和更具临床相关性的方法来评估实验大鼠的自发吗啡戒断。此外，持续性炎性疼痛大鼠的戒断增强表明，疼痛患者可能特别容易出现阿片类药物的戒断。
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 8 days prior to implantation of two 75 mg morphine or placebo pellets. The pellets were removed 3 or 5 days later to induce spontaneous withdrawal. In normal pain-free rats, removal of the morphine pellets depressed wheel running for 48 h 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 3 days of treatment depressed wheel running in these rats for over 6 days. 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.