Physical dependence on morphine and other opioids (e.g. heroin) is a significant problem with substantial medical, economic, and social consequences. At present, our understanding of the central nervous system (CNS) correlates of opioid dependence is far from complete despite significant increases in our knowledge of basic changes in brain function produced by opioids, and of an increasing number of interacting peptide and non-peptide neural systems that may be involved in opioid dependence. Our broad objective is to utilize the ground squirrel hibernator as a model system for identifying the essential opioid-induced changes in CNS function that contribute to the development of physical dependence. The value of this particular model is that it displays a selectively reversible (i.e. hibernation-related) suppression of the development of morphine dependence while retaining morphine agonist (e.g. antinociceptive) action. Accordingly, this proposal will use behavioral and dependence/abstinence; in vivo microdialysis; HPLC; receptor binding assay; immunohistochemistry; radioimmunoassay) to test three specific hypotheses regarding changes in the neurochemical parameters of the hibernating brain that are of likely importance to the suppression of morphine physical dependence: A. Hibernation is associated with a reduction in the binding parameters (affinity and/or number of mu, delta, and/or kappa opioid receptors. B. Hibernation is associated with a decrease in the CNS regional content and/or activity of peptides that exhibit functional antagonism of opioid action (i.e., antiopioid peptides such as neuropeptide FF). C. Hibernation is associated with changes in the performance of the dopamine system in the striatum that reduce perturbation by opioids. This work should provide new and important information on the mechanisms underlying opioid dependence. Beyond this, knowledge of these hibernation-related adaptations could lead to clinically useful drug agents that block the dependence -producing effects of opioid compounds. This research provides an opportunity for students to become involved in a multifaceted biomedical research problem. Exposure to a variety of techniques from the molecular to the organismal level in a team effort approach will encourage future career development in the biomedical sciences.
