The goal of this research project is to understand neural and molecular mechanisms of thermal hyperalgesia associated with narcotic tolerance. Recent investigations have indicated that thermal hyperalgesia develops in association with the development of narcotic tolerance and that excitatory amino acid (EAA) receptor activation and subsequent intracellular second messenger systems may play a critically important role in central nervous system mechanisms of thermal hyperalgesia associated with narcotic tolerance. Thus, multidisciplinary approaches including behavioral, pharmacological, autoradiographic, and immunocytochemical methods will be used to accomplish 3 specific aims: (l) To clarify the time course and dose-response relationships of morphine treatment as well as the role of the opiate kappa receptor in the development of thermal hyperalgesia associated with narcotic tolerance; (2) To determine the role of EAA receptors (both ionotropic and metabotropic EAA receptors) and their relationships in the development and expression of the thermal hyperalgesia; and (3) To determine the role of EAA receptor mediated changes in intracellular protein kinase C and nitric oxide and their relationships in the development and expression of the thermal hyperalgesia. This proposed work will provide novel and important information on neural and molecular mechanisms of hyperalgesia that may be common to thermal hyperalgesia associated with the development of narcotic tolerance in particular and with neurogenic and inflammatory etiologies in general. Because of the intimate relationship between narcotic tolerance and associated thermal hyperalgesia as well as potential interrelations between hyperalgesia induced by narcotic treatment and nerve (tissue) injury or inflammation, the results of this work may help to improve clinical utility of narcotic analgesics in treatment of chronic pain states. In addition, the results from assessment of the roles of EAA receptors, protein kinase C, and nitric oxide will provide insights into the neurobiology of narcotic tolerance which could result in additional clinical applications.
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