1. DETERMINATION OF THE RECEPTOR TYPES INVOLVED IN HEROIN ACTION IN THE BRAIN AND SPINAL CORD. In the brain of Swiss Webster mice intracerebroventricular (i.c.v.) heroin acts on delta receptors (like DPDPE) and acts like the mu agonist DAMGO in the spinal cord. In ICR mice, heroin activates supraspinal and spinal mu receptors (DAMGO). Because the receptors involved are different from those activated by morphine, purpose is: (a) In vivo studies in mice will determine if 6-monoacetyl morphine, a metabolic, has selectivity of receptor action like heroin, morphine or neither. (b) In vitro receptor binding studies will determine receptor selectivity for heroin, 6MAM and morphine. (c) Cross breeding genetic studies will determine genetic or epigenetic factors for control of phenotypic receptor specificity. 2. THE ROLE OF THE SPINAL DYNORPHIN A )1-17) ANTIANALGESIC SYSTEM IN OPIOID TOLERANCE. Some agonists in mice not only activate analgesic but also spinal antianalgesic system mediated by dynorphin A (1-17). Single doses s.c. morphine pretreatment desensitizes the spinal cord to the antianalgesic action of dynorphin A (1-17). Intrathecal (i.t.) dynorphin A at femtomole doses antagonizes analgesic component. Studies will determine: (a) By i.c.v. and i.t. morphine pretreatment, whether desensitization occurs by release of spinal dynorphin A and (b) Relationship of desensitization of the dynorphin system and development of tolerance to opioids in mice with morphine pellet implantation or undergoing withdrawal after morphine pellet removal. 3. THE EFFECT OF NALOXONE AND OTHER OPIOID ANTAGONISTS ON THE ANTIANALGESIC DYNORPHIN A (1-17) SYSTEM. Evidence indicates that naloxone and norbinaltorphimine, opioid antagonists, also release spinal dynorphin A (1- 17). Implications of this finding will be investigating by: (a) Experiments to further demonstrate that naloxone and nor-BNI release spinal dynorphin A (1-17) and (b) Other implications of dynorphin release by chronic administration of opioid antagonist and increased sensitivity to opioid agonists.
