McDaid John, Dallimore Jeanine E, Mackie Alexander R, Napier T Celeste
Department of Pharmacology and Experimental Therapeutics, Loyola University Chicago School of Medicine, Maywood, IL 60153, USA.
Neuropsychopharmacology. 2006 Jun;31(6):1212-26. doi: 10.1038/sj.npp.1300854.
Activation of mu-opioid receptors in the ventral pallidum (VP) is important for the induction of behavioral sensitization to morphine in rats. The present study was designed to ascertain if neurons within the VP demonstrate sensitization at a time when morphine-induced behavioral sensitization occurred (ie 3 or 14 days after five once-daily injections of 10 mg/kg i.p. morphine) in rats. Western blotting was used to evaluate transcription factors altered by opiates, CREB and deltaFosB. CREB levels did not change in the VP, but there was a significant decrease in levels of its active, phosphorylated form (pCREB) at both 3- and 14-days withdrawal. DeltaFosB levels were elevated following a 3-day withdrawal, but returned to normal by 14 days. This profile also was obtained from nucleus accumbens tissue. In a separate group of similarly treated rats, in vivo electrophysiological recordings of VP neuronal responses to microiontophoretically applied ligands were carried out after 14-days withdrawal. The firing rate effects of local applications of morphine were diminished in rats withdrawn from i.p. morphine. Repeated i.p. morphine did not alter GABA-mediated suppression of firing, or the rate enhancing effects of the D1 dopamine receptor agonist SKF82958 or glutamate. However, VP neurons from rats withdrawn from repeated i.p. morphine showed a higher propensity to enter a state of depolarization inactivation to locally applied glutamate. Overall, these findings reveal that decreased pCREB in brain regions such as the VP accompanies persistent behavioral sensitization to morphine and that this biochemical alteration may influence the excitability of neurons in this brain region.
腹侧苍白球（VP）中μ-阿片受体的激活对于大鼠对吗啡行为敏化的诱导很重要。本研究旨在确定在大鼠出现吗啡诱导的行为敏化时（即每天腹腔注射10mg/kg吗啡，连续注射5天，3天或14天后），VP内的神经元是否表现出敏化。采用蛋白质免疫印迹法评估阿片类药物、CREB和deltaFosB改变的转录因子。VP中的CREB水平没有变化，但在撤药3天和14天时，其活性磷酸化形式（pCREB）的水平显著降低。撤药3天后，DeltaFosB水平升高，但到14天时恢复正常。伏隔核组织也得到了类似的结果。在另一组经过类似处理的大鼠中，撤药14天后对VP神经元对微量离子导入配体的反应进行了体内电生理记录。腹腔注射吗啡撤药后的大鼠，局部应用吗啡对放电频率的影响减弱。反复腹腔注射吗啡并未改变GABA介导的放电抑制，或D1多巴胺受体激动剂SKF82958或谷氨酸的频率增强作用。然而，反复腹腔注射吗啡撤药后的大鼠的VP神经元对局部应用谷氨酸进入去极化失活状态的倾向更高。总体而言，这些发现表明，在诸如VP等脑区中pCREB的降低与对吗啡的持续行为敏化相伴，并且这种生化改变可能影响该脑区神经元的兴奋性。
