Van Bockstaele Elisabeth J, Qian Yaping, Sterling Robert C, Page Michelle E
Thomas Jefferson University, Department of Neurosurgery, Farber Institute for Neurosciences, Philadelphia, PA 19107, United States.
Prog Neuropsychopharmacol Biol Psychiatry. 2008 May 15;32(4):1048-56. doi: 10.1016/j.pnpbp.2008.02.004. Epub 2008 Mar 25.
The administration of low dose opioid antagonists has been explored as a potential means of detoxification in opiate dependence. Previous results from our laboratory have shown that concurrent administration of low dose naltrexone in the drinking water of rats implanted with subcutaneous morphine pellets attenuates behavioral and biochemical signs of withdrawal in brainstem noradrenergic nuclei. Noradrenergic projections originating from the nucleus tractus solitarius (NTS) and the locus coeruleus (LC) have previously been shown to be important neural substrates involved in the somatic expression of opiate withdrawal. The hypothesis that low dose naltrexone treatment attenuates noradrenergic hyperactivity typically associated with opiate withdrawal was examined in the present study by assessing norepinephrine tissue content and norepinephrine efflux using in vivo microdialysis coupled to high performance liquid chromatography (HPLC) with electrochemical detection (ED). The frontal cortex (FC), amygdala, bed nucleus of the stria terminalis (BNST) and cerebellum were analyzed for tissue content of norepinephrine following withdrawal in morphine dependent rats. Naltrexone-precipitated withdrawal elicited a significant decrease in tissue content of norepinephrine in the BNST and amygdala. This decrease was significantly attenuated in the BNST of rats that received low dose naltrexone pre-treatment compared to controls. No significant difference was observed in the other brain regions examined. In a separate group of rats, norepinephrine efflux was assessed with in vivo microdialysis in the BNST or the FC of morphine dependent rats or placebo treated rats subjected to naltrexone-precipitated withdrawal that received either naltrexone in their drinking water (5 mg/L) or unadulterated water. Following baseline dialysate collection, withdrawal was precipitated by injection of naltrexone and sample collection continued for an additional 4 h. At the end of the experiment, animals were transcardially perfused and the brains were removed for verification of probe placement. Low dose naltrexone pre-treatment significantly attenuated withdrawal-induced increases of extracellular norepinephrine in the BNST, with a smaller effect in the FC. These findings suggest that alterations in norepinephrine release associated with withdrawal may be attenuated in forebrain targets of noradrenergic brainstem neurons that may underlie reduced behavioral signs of withdrawal following low dose naltrexone administration.
低剂量阿片类拮抗剂的给药已被探索作为阿片类药物依赖解毒的一种潜在手段。我们实验室先前的结果表明，在皮下植入吗啡丸的大鼠饮用水中同时给予低剂量纳曲酮，可减轻脑干去甲肾上腺素能核团中戒断的行为和生化体征。先前已表明，起源于孤束核（NTS）和蓝斑（LC）的去甲肾上腺素能投射是参与阿片类药物戒断躯体表现的重要神经基质。在本研究中，通过使用与高效液相色谱（HPLC）联用的电化学检测（ED）的体内微透析评估去甲肾上腺素组织含量和去甲肾上腺素流出，检验了低剂量纳曲酮治疗减轻通常与阿片类药物戒断相关的去甲肾上腺素能活动亢进的假设。在吗啡依赖大鼠戒断后，分析额叶皮质（FC）、杏仁核、终纹床核（BNST）和小脑的去甲肾上腺素组织含量。纳曲酮诱发的戒断导致BNST和杏仁核中去甲肾上腺素组织含量显著降低。与对照组相比，接受低剂量纳曲酮预处理的大鼠BNST中的这种降低显著减弱。在检查的其他脑区未观察到显著差异。在另一组大鼠中，通过体内微透析评估吗啡依赖大鼠或接受纳曲酮诱发戒断的安慰剂处理大鼠的BNST或FC中的去甲肾上腺素流出，这些大鼠在饮用水中接受纳曲酮（5 mg/L）或未掺杂水。在收集基线透析液后，通过注射纳曲酮诱发戒断，并继续收集样本4小时。实验结束时，对动物进行心脏灌注，并取出大脑以验证探针放置。低剂量纳曲酮预处理显著减弱了戒断诱导的BNST细胞外去甲肾上腺素的增加，在FC中的作用较小。这些发现表明，与戒断相关的去甲肾上腺素释放改变可能在去甲肾上腺素能脑干神经元的前脑靶点中减弱，这可能是低剂量纳曲酮给药后戒断行为体征减轻的基础。
