Avram Goldstein - US grants

This is an application for supplemental funding for a program-project grant for laboratory and human studies on the biochemical basis of opiate addiction, especially on endorphins and opiate receptors. The grant includes a core support element that funds general laboratory support as well as secretarial and computer services. There are four projects. The first project undertakes to apply a radioimmunoassay developed in our laboratory to measure beta-endorphin in blood plasma and cerebrospinal fluid of normals and chronic pain patients, patients receiving acupuncture, psychotic patients, and heroin addicts in methadone and naltrexone maintenance. The second project undertakes to continue work on characterizing the distribution and physiological role of dynorphin, an opiod peptide recently discovered in our laboratory. The third project is to study effects of chronic naloxone infusion in human volunteers, and also to examine the possibility that endorphins mediate placebo responses. The fourth project undertakes to elucidate the role of membrane lipids in the function of opiate receptors, following up discoveries in our laboratory concerning the inactivation of opiate receptors by lipid peroxidation. Although approved for renewal by the IRG, the grant suffered massive and crippling budget cuts that would have effectively destroyed its purpose. The present application is a detailed justification of our request that many (though not all) of these budget cuts be restored.

The dynorphins comprise one of the three families of opioid peptides. They are found throughout the nervous system, they have diverse physiologic functions. They are highly selective for one of the opioid receptor types, the Kappa receptor. We shall carry out five projects -- four of them ongoing now, one of them (#2 below) new. 1. Continue and complete our development of valid type-specific binding assays in order to study the distribution and function of the Kappa receptors, and to guide the testing of new and type-selective opioids with possible therapeutic value. 2. Attempt the cloning of Kappa receptors (in collaboration with a genetic engineering group) in order to learn their primary structure and molecular function. 3. Continue our studies on dynorphin-produced analgesia at the spinal cord level, to learn more about the role of dynorphins in normal pain regulation and in acupuncture analgesia. 4. Purify and further characterize the unique processing enzyme (convertase) that cleaves a precursor peptide specifically to yield dynorphin B. 5. Attempt to demonstrate biosynthesis of the novel morphinelike opiates (including morphine itself) that we have isolated from beef brain and adrenal, the structures of which are presently being determined.