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的相互作用，我提出了下丘脑-垂体-肾上腺（HPA）轴在这些相互作用中的作用。最近，我已经证明，长期吗啡治疗产生深刻和持久的变化，垂体肾上腺反应约束压力。经历急性吗啡戒断的大鼠的HPA轴活动与在抑郁症患者中观察到的相似，而经历慢性吗啡戒断的大鼠的HPA轴活动与在创伤后应激障碍（PTSD）患者中观察到的相似。本文提出的研究将整合生理学，药理学和内分泌学的方法来检查吗啡诱导的HPA轴功能变化的发展和恢复。将在吗啡依赖大鼠中检查基础和应激条件下HPA轴功能所涉及和必需的各种神经激素和受体系统的变化的模式、程度和时程。还将研究皮质酮分泌过多、负反馈系统敏感性改变以及吗啡处理动物中观察到的改良应激反应中易化神经元通路的募集的作用。这些研究可能阐明HPA轴功能改变在药物依赖、抑郁和PTSD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.