title: Comparison of peptidic and nonpeptidic delta-opioid agonists on guanosine 5'-O-(3-[35S]thio)triphosphate ([35S]GTPgammaS) binding in brain slices from Sprague-Dawley rats.
abstract: Previous studies have demonstrated that peptidic and nonpeptidic delta-opioid receptor agonists have different effects depending on the measure. For example, nonpeptidic delta-opioid agonists, but not peptidic agonists, produce convulsions in rats, and in vitro studies suggested that peptidic and nonpeptidic delta-opioid agonists might have differential mechanisms of receptor downregulation. The present study evaluated potential differences between peptidic and nonpeptidic delta-opioid agonists in their ability to activate G proteins using guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) autoradiography experiments in rat brain slices. The peptidic agonist [d-Pen(2),d-Pen(5)]-enkephalin and the nonpeptidic agonist (+)BW373U86 [(+)-4-[alpha(R)-alpha-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide] demonstrated concentration-dependent increases in [(35)S]GTPgammaS binding that were attenuated by the delta-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 delta-opioid compounds were evaluated for their agonist activity in this assay. These data suggested that differences between peptidic and nonpeptidic delta-opioid agonists in behavioral studies were most likely caused by differences in agonist efficacy. Finally, these data also revealed that [(35)S]GTPgammaS autoradiography could be used to compare efficacy differences among agonists across various brain regions in rat brain slices.
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109-0632, USA.
authors.forename: Emily M
authors.initials: EM
authors.lastname: Jutkiewicz
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Walker
authors.forename: John E
authors.initials: JE
authors.lastname: Folk
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
authors.forename: Philip S
authors.initials: PS
authors.lastname: Portoghese
authors.forename: James H
authors.initials: JH
authors.lastname: Woods
authors.forename: John R
authors.initials: JR
authors.lastname: Traynor
mesh_terms: D000818:Animals; D001345:Autoradiography; D001549:Benzamides / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D020881:Enkephalin, D-Penicillamine (2,5)- / Q000494:pharmacology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism*; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000819:agonists*
chemical_list: D001549:Benzamides; D010879:Piperazines; D017465:Receptors, Opioid, delta; C083877:BW 373U86; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D020881:Enkephalin, D-Penicillamine (2,5)-