• S R Childers, R Xiao, L Vogt, and L J Sim.
• Department of Physiology and Pharmacology, Center for the Neurobiological Investigation of Drug Abuse, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA. childers@wfubmc.edu
• Biochem. Pharmacol. 1998 Jul 1;56(1):113-20.

AbstractAlthough only one gene for kappa opioid receptors has been cloned to date, kappa1 and kappa2 receptors have been defined pharmacologically, with drugs such as bremazocine binding to both putative kappa receptor subtypes. To examine whether kappa receptor subtypes can be distinguished at the level of the G-protein, the ability of the kappa1 agonist (trans-(dl)-3,4-dichloro-N- methyl-N-[2-(1 -pyrrolidinyl)cyclohexyl]-benzeneacetamide) methane sulfonate (U-50488H) to stimulate [35S]guanosine-5'-O-(gamma-thio)-triphosphate ([35S]GTPgammaS) binding in guinea pig brain was compared with that of bremazocine and dynorphin. In membranes prepared from guinea pig striatum, both bremazocine and U-50488H stimulated [35S]GTPgammaS binding with the same relative efficacy, while dynorphin produced at least two-fold greater efficacy than the other two agonists. In vitro autoradiography of agonist-stimulated [35S]GTPgammaS binding revealed similar regional distributions of bremazocine- and U-50488H-activated G-proteins. In striatal membranes, the kappa antagonist nor-binaltorphimine (nor-BNI) blocked both bremazocine- and U-50488H-stimulated [35S]GTPgammaS binding with similar Ke values. In agonist additivity experiments, the stimulation of [35S]GTPgammaS binding by the delta agonist [D-pen2'5, p-Cl-Phe4]enkephalin (p-Cl-DPDPE) was approximately additive with the two kappa agonists. Stimulation of [35S]GTPgammaS binding by the mu agonist [D-Ala2, N-Me4, Gly5-ol]-enkephalin (DAMGO) was additive with U-50488H, but not with bremazocine, reflecting the mu antagonist properties of this compound. The combination of bremazocine and U-50488H together produced no greater stimulation of binding than either agonist alone, indicating that they were binding to the same site. These results demonstrate that bremazocine and U-50488H activate G-proteins in guinea pig brain through the same receptor, and suggest that kappa2 receptors are not coupled through the same signal transduction mechanisms as kappa1 receptors.

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