Morphine dependence and HPA axis activity

流行病学、临床和实验室研究表明阿片类药物和压力之间存在相互作用，我已经提出了下丘脑-垂体-肾上腺(HPA)轴在这些相互作用中的作用。最近，我证明了慢性吗啡治疗会导致脑下垂体-肾上腺对束缚压力的反应发生深刻而持久的变化。急性吗啡戒断大鼠的HPA轴活动与抑郁症患者相似，而慢性吗啡戒断大鼠的HPA轴活动与创伤后应激障碍(PTSD)患者的HPA轴活动相似。这里提出的研究将结合生理学、药理学和内分泌学的方法来检查吗啡诱导的HPA轴功能的发展和恢复。在基础和应激条件下，我们将研究与HPA轴功能有关的各种神经激素和受体系统的变化模式、程度和时间进程。还将研究皮质酮高分泌、负反馈系统的敏感性改变以及易化神经通路在吗啡处理动物中观察到的改良应激反应中的作用。这些研究可能阐明HPA轴功能改变在药物依赖、抑郁和创伤后应激障碍的神经生物学中的作用。

Epidemiological, clinical, and laboratory studies have suggested an interaction between opiods and stress, and I have proposed a role for the hypothalamic-pituitary-adrenal (HPA) axis in these interactions. Recently, I have demonstrated that chronic morphine treatment produces profound and long-lasting changes in the pituitary-adrenal responses to restraint stress. HPA axis activity in rats undergoing acute morphine withdrawal resembles that observed in depressed patients, whereas HPA axis activity in rats undergoing chronic morphine withdrawal mimics that observed in patients suffering from post-traumatic stress disorder (PTSD). The studies proposed herein will integrate physiological, pharmacological, and endocrinological approaches to examine the development and recovery of morphine-induced changes in HPA axis function. The pattern, extent, and time course of changes in various neurohormone and receptor systems that are involved in and necessary for HPA axis function under basal and stress conditions will be examined in morphine-dependent rats. The role of corticosterone hypersecretion, altered sensitivity of negative feedback systems, and recruitment of facilitatory neuronal pathways in the modified stress responses observed in morphine-treated animals will also be examined. These studies may elucidate the role of altered HPA axis function in the neurobiology of drug dependence, depression, and PTSD.