Ethanol Reversal of Tolerance to the Respiratory Depressant Effects of Morphine.
Ethanol Reversal of Tolerance to the Respiratory Depressant Effects of Morphine.
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DOI：
10.1038/npp.2015.201
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发表时间：
2016-02
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影响因子：
--
通讯作者：
Henderson G
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文献类型：
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作者：
Hill R;Lyndon A;Withey S;Roberts J;Kershaw Y;MacLachlan J;Lingford-Hughes A;Kelly E;Bailey C;Hickman M;Henderson G
阿片类药物是与非故意药物过量相关的最常见药物。呼吸抑制导致死亡。长期使用阿片类药物导致耐受性的发展，但耐受性的程度被认为因药物的不同作用而异。许多阿片类药物成瘾者经常饮酒（乙醇），对阿片类药物过量死亡的尸检分析显示，血液吗啡和乙醇水平之间呈负相关。在本研究中，我们确定了乙醇是否降低了对阿片类药物呼吸抑制作用的耐受性。用阿片类药物（吗啡、美沙酮或丁丙诺啡）处理小鼠长达6天。在体积描记器室中，在呼吸5% CO2的空气中自由移动的动物中测量呼吸。抗伤害感受（镇痛）被测量为从热刺激移除尾部的潜伏期。通过测量对吗啡的激发剂量（10 mg/kg i. p.）的反应来评估阿片耐受性。耐受性发展到吗啡的呼吸抑制作用，但在一个缓慢的速度比耐受其镇痛作用。单独低剂量乙醇（0.3 mg/kg）不会抑制呼吸，但在长期吗啡处理的动物中，当乙醇与吗啡激发共同给药时，观察到呼吸抑制。乙醇并没有改变大脑中吗啡的水平。相比之下，在美沙酮或丁丙诺啡治疗的动物中，当乙醇与吗啡激发一起沿着给药时，未观察到呼吸抑制。由于海洛因在人体内转化为吗啡，乙醇选择性逆转吗啡耐受可能是海洛因过量死亡的一个促成因素。
Opioids are the most common drugs associated with unintentional drug overdose. Death results from respiratory depression. Prolonged use of opioids results in the development of tolerance but the degree of tolerance is thought to vary between different effects of the drugs. Many opioid addicts regularly consume alcohol (ethanol), and post-mortem analyses of opioid overdose deaths have revealed an inverse correlation between blood morphine and ethanol levels. In the present study, we determined whether ethanol reduced tolerance to the respiratory depressant effects of opioids. Mice were treated with opioids (morphine, methadone, or buprenorphine) for up to 6 days. Respiration was measured in freely moving animals breathing 5% CO2 in air in plethysmograph chambers. Antinociception (analgesia) was measured as the latency to remove the tail from a thermal stimulus. Opioid tolerance was assessed by measuring the response to a challenge dose of morphine (10 mg/kg i.p.). Tolerance developed to the respiratory depressant effect of morphine but at a slower rate than tolerance to its antinociceptive effect. A low dose of ethanol (0.3 mg/kg) alone did not depress respiration but in prolonged morphine-treated animals respiratory depression was observed when ethanol was co-administered with the morphine challenge. Ethanol did not alter the brain levels of morphine. In contrast, in methadone- or buprenorphine-treated animals no respiratory depression was observed when ethanol was co-administered along with the morphine challenge. As heroin is converted to morphine in man, selective reversal of morphine tolerance by ethanol may be a contributory factor in heroin overdose deaths.