Role of HPA activation in opioid dependence and withdrawal

描述(申请人提供)：阿片类药物滥用仍然是一个严重的公共卫生问题。阿片类药物有很高的滥用和依赖倾向，滥用可能导致过量和死亡。成功的药物滥用治疗常常因为难以促进当前吸毒者的持续戒毒而受到阻碍。导致阿片类药物持续滥用和戒断(复发)后恢复使用阿片类药物的因素很多。对这些因素的了解将有助于开发更有效的治疗方法。长期使用阿片类药物与神经内分泌功能，特别是下丘脑-垂体-肾上腺轴(HPA)活动的显著变化有关，这些变化与戒断和持续使用药物的出现有关。虽然HPA激活和戒断之间的联系已经建立，但还不知道(S)HPA激活可能扮演什么角色。一种可能性是，HPA的激活作为一种触发因素，引发了一些戒断表现，以及与戒断相关的效应，在 转向，促进吸毒/复发。这项应用研究将检测阿片依赖和戒断过程中HPA轴活性的变化，并比较HPA轴活性的变化与对行为和生理指标的影响。因此，这项研究将为未来的研究奠定基础，研究HPA轴的激活可能在调节从戒酒到吸毒的转变过程中发挥作用。目标1的研究将确定吗啡和纳曲酮对HPA轴活动以及行为和生理指标的急性影响。AIM 2中的研究将检查在每天给吗啡期间和停止每日吗啡治疗后，在行为、生理和内分泌测量方面发生的变化。在不同的吗啡治疗期间，HPA轴活动的变化将与行为和生理指标进行比较，这些指标已被确定为阿片依赖和戒断的可靠指标。这些研究将为反复接触阿片类药物引起的HPA功能变化提供一套基础性研究。此外，还提出了博士后培训计划，其中包括一项严格的结构活动计划，旨在促进申请者从博士后实习生过渡到独立研究人员。

DESCRIPTION (provided by applicant): Opioid abuse continues to be a significant public health problem. Opioids have high abuse and dependence liability and their misuse can lead to overdose and death. Successful treatment of drug abuse is often hindered by difficulty in promoting sustained abstinence in current drug users. Many factors contribute to continued opioid abuse and the resumption of opioid use after periods of abstinence (relapse). An understanding of these factors will contribute to the development of more effective treatments. Prolonged use of opioids has been associated with significant changes in neuroendocrine function, particularly in activity of the hypothalamic- pituitary-adrenal (HPA) axis, and these changes have been linked to the emergence of withdrawal and continued drug use. Although the association between HPA activation and withdrawal has been established, it is not known exactly what roles(s) HPA activation might play. One possibility is that HPA activation serves as a trigger that elicits some manifestations of withdrawal and that withdrawal-associated effects, in turn, promote drug taking/relapse. Studies in this application will examine changes in HPA axis activity during the development of opioid dependence and withdrawal and compare changes in HPA axis activity with effects on behavioral and physiological measures. Consequently, this research will set the stage for future studies examining the role that activation of the HPA axis might serve in mediating the transition from abstinence to drug taking. Studies in Aim 1 will determine the acute effects of morphine and of naltrexone on HPA axis activity and behavioral and physiological measures. Studies in Aim 2 will examine changes that occur in behavioral, physiological, and endocrinological measures, during daily administration of morphine and following discontinuation of daily morphine treatment. Changes in HPA axis activity during different morphine treatments will be compared to behavioral and physiological measures that have been established as reliable indicators of opioid dependence and withdrawal. These studies will provide foundational set of studies on the changes in HPA function that occur as a result of repeated exposure to opioids. Moreover, a postdoctoral training plan is proposed that involves a rigorous program of structure activities designed to facilitate the applicant's transitin from postdoctoral trainee to an independent investigator.