Taylor J R, Elsworth J D, Garcia E J, Grant S J, Roth R H, Redmond D E
Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06510.
Psychopharmacology (Berl). 1988;96(1):121-34. doi: 10.1007/BF02431544.
Clonidine, an alpha-2-adrenergic agonist, suppresses signs of opiate withdrawal in animals and in man. Electrical or chemical stimulation of the nucleus locus coeruleus (LC) increases noradrenergic activity and brain concentration of the noradrenergic metabolite MHPG, and produces many signs of opiate withdrawal. Thus, clonidine's ability to attenuate withdrawal might be due to the reduction of noradrenergic neuronal activity originating in the LC, but additional alpha-2-adrenergic receptors throughout the body and other mechanisms may also play a role. The present study explored the neuroanatomical and pharmacological selectivity of alpha-2-adrenergic receptors of the LC in the anti-withdrawal action of clonidine. Experiment 1 tested the hypothesis that behavioral and biochemical measures of naloxone-precipitated withdrawal from morphine would be blocked by infusions of clonidine (0.6 or 2.4 micrograms/microliters) into the LC. Significant reductions were observed in the occurrence of diarrhea, ptosis, weight loss and wet-dog shakes. Clonidine also reversed the naloxone-precipitated increase in hippocampus MHPG concentration. In experiment 2 subjects received an LC infusion or IP injection of a non-lipophilic alpha-2-agonist (ST-91), which does not penetrate the blood-brain barrier, or of clonidine into the dorsal parabrachial nucleus (DPB) to test the selectivity of the effects of clonidine infusions into the LC. ST-91 infusions into the LC reduced several of the observed withdrawal signs and increased others (e.g., jumping). Although peripheral injections of ST-91 attenuated some of the checked signs associated with naloxone-precipitated withdrawal, the frequency of wet-dog shakes was not reduced. ST-91 infusions into the LC, but not systemic ST-91 administration, prevented the withdrawal-induced increase in hippocampus MHPG concentration. Clonidine infused lateral to the LC into the DPB did not significantly attenuate withdrawal or reduce hippocampus MHPG levels. These results provide behavioral and biochemical evidence to support the suggestion that clonidine significantly attenuates naloxone-precipitated withdrawal through an interaction with noradrenergic neurons located in the vicinity of the LC.
可乐定是一种α2-肾上腺素能激动剂，可抑制动物和人类的阿片类药物戒断症状。对蓝斑核（LC）进行电刺激或化学刺激会增加去甲肾上腺素能活性以及去甲肾上腺素能代谢产物3-甲氧基-4-羟基苯乙二醇（MHPG）的脑内浓度，并产生许多阿片类药物戒断症状。因此，可乐定减轻戒断症状的能力可能是由于源自LC的去甲肾上腺素能神经元活动减少，但全身其他的α2-肾上腺素能受体和其他机制也可能起作用。本研究探讨了LC的α2-肾上腺素能受体在可乐定抗戒断作用中的神经解剖学和药理学选择性。实验1检验了以下假设：向LC内注射可乐定（0.6或2.4微克/微升）可阻断纳洛酮诱发的吗啡戒断的行为和生化指标。腹泻、眼睑下垂、体重减轻和湿狗样抖动的发生率显著降低。可乐定还逆转了纳洛酮诱发的海马体中MHPG浓度升高。在实验2中，受试者接受向LC内注射或腹腔注射一种不能穿透血脑屏障的非亲脂性α2-激动剂（ST-91），或向臂旁背核（DPB）注射可乐定，以测试向LC内注射可乐定的效果的选择性。向LC内注射ST-91可减少一些观察到的戒断症状，但也增加了其他症状（如跳跃）。虽然外周注射ST-91减轻了一些与纳洛酮诱发的戒断相关的检查症状，但湿狗样抖动的频率并未降低。向LC内注射ST-91可防止戒断引起的海马体中MHPG浓度升高，但全身给予ST-91则无此作用。向LC外侧的DPB注射可乐定并不能显著减轻戒断症状或降低海马体中MHPG水平。这些结果提供了行为和生化证据，支持以下观点：可乐定通过与位于LC附近的去甲肾上腺素能神经元相互作用，显著减轻纳洛酮诱发的戒断症状。
