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NEUROPHARMACOLOGY

Comparison of Peptidic and Nonpeptidic -Opioid Agonists on Guanosine 5'-O-(3-[³⁵S]thio)triphosphate ([³⁵S]GTPS) Binding in Brain Slices from Sprague-Dawley Rats

Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan (E.M.J., N.P.W., J.H.W., J.R.T.); Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (J.E.F., K.C.R.); and Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (P.S.P.)

Previous studies have demonstrated that peptidic and nonpeptidic -opioid receptor agonists have different effects depending on the measure. For example, nonpeptidic -opioid agonists, but not peptidic agonists, produce convulsions in rats, and in vitro studies suggested that peptidic and nonpeptidic -opioid agonists might have differential mechanisms of receptor downregulation. The present study evaluated potential differences between peptidic and nonpeptidic -opioid agonists in their ability to activate G proteins using guanosine 5'-O-(3-[³⁵S]thio)triphosphate ([³⁵S]GTPS) autoradiography experiments in rat brain slices. The peptidic agonist [D-Pen²,D-Pen⁵]-enkephalin and the nonpeptidic agonist (+)BW373U86 [(+)-4-[(R)--[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide] demonstrated concentration-dependent increases in [³⁵S]GTPS binding that were attenuated by the -opioid antagonist naltrindole. (+)BW373U86 was more potent and efficacious than the peptidic agonist, and this difference remained consistent across brain regions where significant stimulation was observed. In addition, multiple -opioid compounds were evaluated for their agonist activity in this assay. These data suggested that differences between peptidic and nonpeptidic -opioid agonists in behavioral studies were most likely caused by differences in agonist efficacy. Finally, these data also revealed that [³⁵S]GTPS autoradiography could be used to compare efficacy differences among agonists across various brain regions in rat brain slices.

Address correspondence to: Dr. John R. Traynor, 1301 Medical Science Research Building 3, Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109-0632. E-mail: jtraynor{at}umich.edu

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