Mannelli Paolo, Gottheil Edward, Peoples James F, Oropeza Veronica C, Van Bockstaele Elisabeth J
Department of Psychiatry and Human Behavior, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Biol Psychiatry. 2004 Aug 15;56(4):261-8. doi: 10.1016/j.biopsych.2004.05.013.
Different regimens of agonist and antagonist drugs have been used in opioid withdrawal management, with variable results. We examined whether administering extremely small quantities of opiate antagonists in the presence of opiate agonist drugs reduces withdrawal expression.
Forty-one male Sprague-Dawley rats were implanted with morphine or placebo pellets for eight days. Starting on day 3, some rats received naltrexone in their drinking water (5 mg/L), or unadulterated water. On day 8, rats were injected with saline or naltrexone (100 mg/kg) and evaluated for behavioral signs of withdrawal. Next, sections through the locus coeruleus (LC) and nucleus of the solitary tract (NTS), brainstem areas exhibiting cellular activation following opiate withdrawal, were processed for c-Fos to detect early gene expression. Finally, the same nuclei were examined for protein kinase A regulatory subunit II (PKA) and phosphorylated cyclic adenosine monophosphate response element binding protein (pCREB), using Western blot analysis.
Withdrawal was attenuated and c-Fos, PKA, and pCREB expression was decreased in the NTS and LC of rats receiving chronic very low doses of naltrexone.
Reduction of withdrawal upon chronic very low naltrexone administration may be due in part to decreased activation of brainstem noradrenergic neurons in morphine dependent rats.
在阿片类药物戒断管理中使用了不同的激动剂和拮抗剂药物方案，结果各异。我们研究了在存在阿片类激动剂药物的情况下给予极少量阿片类拮抗剂是否会减少戒断表现。
将41只雄性Sprague-Dawley大鼠植入吗啡或安慰剂微丸8天。从第3天开始，一些大鼠在饮用水中接受纳曲酮（5毫克/升）或未掺杂的水。在第8天，给大鼠注射生理盐水或纳曲酮（100毫克/千克），并评估戒断的行为体征。接下来，对蓝斑（LC）和孤束核（NTS）进行切片，这两个脑干区域在阿片类药物戒断后会出现细胞激活，对其进行c-Fos处理以检测早期基因表达。最后，使用蛋白质印迹分析检查相同的核中蛋白激酶A调节亚基II（PKA）和磷酸化环磷酸腺苷反应元件结合蛋白（pCREB）。
在接受慢性极低剂量纳曲酮的大鼠的NTS和LC中，戒断症状减轻，c-Fos、PKA和pCREB表达降低。
慢性给予极低剂量纳曲酮后戒断症状减轻，部分原因可能是吗啡依赖大鼠脑干去甲肾上腺素能神经元的激活减少。
