Prevention of precipitated withdrawal symptoms by activating central cholinergic systems during a dependence-producing schedule of morphine in rats
Prevention of precipitated withdrawal symptoms by activating central cholinergic systems during a dependence-producing schedule of morphine in rats
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DOI：
10.1016/s0006-8993(99)02197-6
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发表时间：
2000-01-03
期刊：
影响因子：
2.9
通讯作者：
Gattu, M
中科院分区：
文献类型：
--
作者：
Buccafusco, JJ;Zhang, LC;Gattu, M
该实验室和其他实验室以前的研究表明，中枢胆碱能神经元在吗啡戒断症状的表达中起着重要作用。这项研究旨在确定吗啡对胆碱能神经元的影响是否可以通过正常化来缓解戒断症状。由于这种影响通常是抑制的，我们使用中枢作用的胆碱能激动剂来增强慢性吗啡注射期间的中枢胆碱能张力。采用动脉内注射(i.a.)增加吗啡浓度(35-100 mg kg(-1)day(-1))超过5天。内务部。注射0.5 mg/kg纳洛酮可引起深刻的戒断反应，包括持续60分钟的平均动脉压(MAP)显著升高，心率(HR)短时间加快，以及典型的阿片类药物戒断症状。在不同的大鼠组中，在吗啡注射的同时，每日单次注射无毒剂量的乙酰胆碱酯酶(AChE)抑制剂二异丙基氟磷酸(DFP)(50和250 mU g/kg)。DFP处理组大鼠的纳洛酮诱导的升压反应的表达显著减少。选择性外周作用的AChE抑制剂ECHO硫代磷酸不能复制DFP的明显的抗戒断作用，尽管这两种化合物都有效地减少了某些其他戒断症状的表达。中枢作用的M胆碱能受体激动剂槟榔碱。结果对戒断症状的抑制更令人印象深刻。虽然不是所有与吗啡戒断相关的症状都是通过中枢胆碱能通路调节的，但这些结果表明，在吗啡给药过程中，中枢胆碱能活动的增强可以在很大程度上抑制对吗啡的身体依赖。(C)2000 Elsevier Science B.V.保留所有权利。
Previous studies in this and other laboratories have suggested an important role for central cholinergic neurons in the expression of morphine withdrawal symptoms. This study was designed to determine whether the symptoms of withdrawal could be mitigated by normalization of the effect of morphine on cholinergic neurons. Since this effect is generally inhibitory, we used centrally acting cholinergic agonists to augment central cholinergic tone during chronic morphine infusion. Rats were made dependent following the intra-arterial (i.a.) infusion of increasing concentrations (35-100 mg kg(-1) day(-1)) of morphine over 5 days. I.a. injection of 0.5 mg/kg of naloxone precipitated a profound withdrawal response that included a dramatic increase in mean arterial pressure (MAP) which was maintained over the 60-min observation period, a short duration increase in heart rate (HR), and characteristic opiate withdrawal symptoms. In separate groups of rats, non-toxic doses (50 and 250 mu g/kg) of the acetylcholinesterase (AChE) inhibitor, diisopropylflurophosphate (DFP) were administered as single daily injections concomitant with the morphine infusion. DFP treated rats, exhibited significantly reduced expression of the naloxone-evoked pressor response. The apparent anti-withdrawal effect of DFP was not reproduced by the selective peripherally acting AChE inhibitor, echothiophate, although both compounds effectively reduced the expression of certain other withdrawal symptoms. The centrally acting muscarinic cholinergic receptor agonist, arecoline. resulted in an el en more impressive suppression of withdrawal symptoms. While not all symptoms associated with morphine withdrawal are mediated via central cholinergic pathways, these results suggest that physical dependence on morphine can be suppressed to a significant degree by the augmentation of central cholinergic activity during morphine administration. (C) 2000 Elsevier Science B.V. All rights reserved.