Role of HPA activation in opioid dependence and withdrawal

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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.