A major research emphasis in the last year has been to utilize the behavior genetics method and a classical pharmacological approach to determine genetic and pharmacological contributions to characteristics important in the acute effects of opioids. In particular, delta-opioid subtypes have recently been proposed based upon differential antagonism and no cross tolerance between the delta-agonists, DPDPE and deltorphin II. In order to determine the existence of delta-receptor subtypes and determine the degree of genetic covariance between the proposed subtypes full dose-response curves for DPDPE and deltorphin II were determined in eight inbred mouse strains. The correlation between sensitivity to DPDPE- and deltorphin II-induced analgesia was not significant thus supporting a pharmacological and genetic separation of the two delta-receptor subtypes. Two inbred strains that lacked a delta-2 response and a strain in which the mu agonist morphine acts like a delta-agonist were used in combination with other inbred strains to investigate the interactions of the delta-2 subtype with delta-1 and mu-agonists. Cross-over pretreatment experiments with the two delta-agonists suggest that deltorphin II is not unique in its pharmacology due to partial agonist properties but is pharmacologically and genetically distinct in its mechanism of action. In the interaction experiments, the 2 strains lacking delta-2 agonist effects and the strain in which morphine acts via delta-mechanisms, deltorphin II did not shift the morphine dose-response curve. Initial biochemical studies done in collaboration with the Clinical Psychopharmacology Section verify the absence of a delta-receptor subtype in the CBA strain and may provide a unique 'd knockout' strain for investigating the role of this d-receptor subtype in the acute and chronic effects of abused drugs. The data provided in these experiments are being compared to transgenic mice that display increased mu-receptor Bmax (superoxide dismutase transgene addition, Molecular Neuropsychiatry Section) in order to explore the in vivo consequences of altered mu and delta receptor regulation on the acute and chronic affects of abused drugs.
