The long-term objective of this proposal is to advance our knowledge of the neurobiology of opiate abuse by understanding how opioids affect mechanisms of neuroendocrine regulation. The current proposal will focus on the endogenous opioid precursor proopiomelanocortin (POMC) in the hypothalamus and its interactions with corticotropin releasing hormone (CRH) which plays a critical role in coordinating the neuroendocrine response to stress. Two POMC derived peptides, beta-endorphin and a-MSH, have important neuroendocrine effects and have been implicated in the stress response and in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. This proposal examines the HPA and cytokine responses to inflammatory stress and on the disruptive effects of opioid drugs on these processes. It focuses on the regulation of POMC and CRH in the hypothalamus of the rat when the HPA axis is activated by inflammatory ;cytokines (IL 1, IL-6 and TNFa). The effect of these cytokines, either administered exogenously or released endogenously in response to endotoxin, on POMC gene expression and peptide levels in the hypothalamus will be studied and the role of POMC peptides in limiting or terminating the effects of these cytokines on the HPA axis will be determined. The effect of treatment with opioid agonists and antagonists on cytokine-CRH-POMC interactions in brain will also be studied. Specifically the ability of chronic morphine treatment and withdrawal to affect basal and IL-l stimulated expression of the CRH gene and its recently cloned receptor will be studied in the hypothalamus and correlated with the functional effects of these treatments on ACTH, corticosterone and IL-6 release in chronically catheterized animals. Neuropeptide gene expression and peptide levels will be studied by sensitive solution hybridization assays, complemented by in situ hybridization, and well characterized radioimmunoassays. These studies should have direct relevance to the clinical problem of drug abuse. Infection, with associated cytokine release, has always been a major complication of intravenous drug abuse even before the era of HIV infection. lt is thus important to know how opioid drug use and withdrawal affect cytokine mediated HPA responses especially since these interactions may also play a critical role in regulating the immune response. The studies outlined in this proposal should provide important new information about the neuroendocrine response to stress which should have broader implications for the regulation of immune function through interactions with the neuroendocrine system.
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