Rasmussen K
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Neuropsychopharmacology. 1995 Dec;13(4):295-300. doi: 10.1016/0893-133X(95)00082-O.
Biochemical, behavioral, and electrophysiologic studies indicate that activation of the noradrenergic cells in the locus coeruleus (LC) plays an important role in the symptoms of opiate withdrawal. Extrinsic factors play a major role in the morphine-withdrawal-induced activation of the LC, but intrinsic factors also play a role. Among the extrinsic factors, a glutamatergic projection from the nucleus paragigantocellularis plays an important role in the withdrawal-induced activation of the LC. N-methyl-D-aspartic acid (NMDA) receptors play at most a minor role in the withdrawal-induced activation of the LC by glutamate; preliminary evidence indicates that alpha-amino-3 hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors play an important role. Whereas NMDA antagonists produce little to no suppression of the activation of the LC during morphine withdrawal, they do suppress many morphine withdrawal symptoms. However, phencyclidinelike side effects may limit the clinical utility of NMDA antagonists. Experiments examining c-fos expression during morphine withdrawal indicate that NMDA antagonists may exert some of their influence on morphine withdrawal symptoms through actions in the forebrain. Pretreatment with the noncompetitive NMDA antagonist MK801 blocks morphine withdrawal-induced increased c-fos expression in the amygdala, but not in the nucleus accumbens, frontal cortex, or hippocampus. Pretreatment with the competitive NMDA antagonist LY274614 (or the alpha2-adrenergic agonist clonidine) blocks morphine withdrawal-induced increased c-fos expression in the amygdala and nucleus accumbens, but not in the frontal cortex or hippocampus. These results help to elucidate some of the neuroanatomy and neurophysiology underlying morphine withdrawal. Further, NMDA antagonists may not be clinically useful for opiate withdrawal due to their side-effects, but AMPA antagonists may be of great benefit for alleviating opiate withdrawal symptoms in humans.
生化、行为和电生理研究表明，蓝斑（LC）中去甲肾上腺素能细胞的激活在阿片类药物戒断症状中起重要作用。外在因素在吗啡戒断诱导的LC激活中起主要作用，但内在因素也发挥作用。在外在因素中，来自巨细胞旁核的谷氨酸能投射在戒断诱导的LC激活中起重要作用。N-甲基-D-天冬氨酸（NMDA）受体在谷氨酸诱导的LC激活中至多起次要作用；初步证据表明，α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体起重要作用。虽然NMDA拮抗剂在吗啡戒断期间对LC激活几乎没有抑制作用，但它们确实能抑制许多吗啡戒断症状。然而，苯环己哌啶样副作用可能会限制NMDA拮抗剂的临床应用。研究吗啡戒断期间c-fos表达的实验表明，NMDA拮抗剂可能通过在前脑的作用对吗啡戒断症状产生一些影响。用非竞争性NMDA拮抗剂MK801预处理可阻断吗啡戒断诱导的杏仁核中c-fos表达增加，但伏隔核、额叶皮质或海马中无此作用。用竞争性NMDA拮抗剂LY274614（或α2-肾上腺素能激动剂可乐定）预处理可阻断吗啡戒断诱导的杏仁核和伏隔核中c-fos表达增加，但额叶皮质或海马中无此作用。这些结果有助于阐明吗啡戒断背后的一些神经解剖学和神经生理学。此外，由于NMDA拮抗剂的副作用，它们可能对阿片类药物戒断在临床上无用，但AMPA拮抗剂可能对减轻人类阿片类药物戒断症状有很大益处。
