MOLECULAR BASIS OF OPIOID PHARMACODYNAMICS

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DESCRIPTION: (Applicant's Abstract) This is a request for a renewal of a Research Scientist Award to allow me to continue to pursue the acquisition of techniques of molecular biology and neuroscience and to allow me to apply them to two NIDA funded research projects. Both projects are designed to test the hypothesis that Excitatory Amino Acid (EAA) receptors mediate the neuronal plasticity that is manifest as opioid tolerance and dependence or as certain types of nociceptive behavior. The first project will use NMDA and non-NMDA receptor antagonists and agonists as well as antisense or ribozymes targeted to NMDA receptors in selected animal behavioral paradigms to demonstrate the role of EAA receptors in opioid tolerance and nociception. Molecular and biochemical techniques will be used to identify and localize to neuroanatomical areas, the changes in gene expression that are associated with opioid tolerance or nociceptive behaviors. To complement and extend these approaches, opioid tolerance, dependence and nociceptive behaviors will be measured in knockout mice engineered with an absent or mutated EAA receptor. The second project will determine, in cultured cells expressing functional NMDA and opioid (mu or delta) receptors, the role of NMDA receptors in the changes that occur in opioid receptor signal transduction as a result of the exposure of these cells to opioids. The acquisition of molecular techniques, including, those related to gene targeting will be accomplished through sabbatical research in a laboratory where I can be directly involved in the design, production and evaluation of EAA receptor knockout mice. This RSA award will also allow me to maintain the reduction in teaching and administrative responsibilities that have for the past four years, significantly increased the time I can devote to enhancing my scientific skills.