Comparison of peptidic and nonpeptidic δ-opioid agonists on guanosine 5′-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding in brain slices from Sprague-Dawley rats

Emily M. Jutkiewicz, Nicholas P. Walker, John E. Folk, Kenner C. Rice, Philip S Portoghese, James H. Woods, John R. Traynor

Research output: Contribution to journalArticle

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Abstract

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

Original languageEnglish (US)
Pages (from-to)1314-1320
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume312
Issue number3
DOIs
StatePublished - Mar 1 2005

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Guanosine 5'-O-(3-Thiotriphosphate)
Opioid Analgesics
Sprague Dawley Rats
Brain
naltrindole
Autoradiography
D-Penicillamine (2,5)-Enkephalin
Narcotic Antagonists
Opioid Receptors
GTP-Binding Proteins
Seizures
Down-Regulation

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Comparison of peptidic and nonpeptidic δ-opioid agonists on guanosine 5′-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding in brain slices from Sprague-Dawley rats. / Jutkiewicz, Emily M.; Walker, Nicholas P.; Folk, John E.; Rice, Kenner C.; Portoghese, Philip S; Woods, James H.; Traynor, John R.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 312, No. 3, 01.03.2005, p. 1314-1320.

Research output: Contribution to journalArticle

Jutkiewicz, Emily M. ; Walker, Nicholas P. ; Folk, John E. ; Rice, Kenner C. ; Portoghese, Philip S ; Woods, James H. ; Traynor, John R. / Comparison of peptidic and nonpeptidic δ-opioid agonists on guanosine 5′-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding in brain slices from Sprague-Dawley rats. In: Journal of Pharmacology and Experimental Therapeutics. 2005 ; Vol. 312, No. 3. pp. 1314-1320.
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abstract = "Previous studies have demonstrated that peptidic and nonpeptidic δ-opioid receptor agonists have different effects depending on the measure. For example, nonpeptidic δ-opioid agonists, but not peptidic agonists, produce convulsions in rats, and in vitro studies suggested that peptidic and nonpeptidic δ-opioid agonists might have differential mechanisms of receptor down-regulation. The present study evaluated potential differences between peptidic and nonpeptidic δ-opioid agonists in their ability to activate G proteins using guanosine 5′-O-(3-[ 35S]thio)triphosphate ([35S]GTPγS) autoradiography experiments in rat brain slices. The peptidic agonist [D-Pen2,D- Pen5]-enkephalin and the nonpeptidic agonist (+)BW373U86 [(+)-4-[α(R)-α-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl] -(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide] demonstrated concentration-dependent increases in [35S]GTPγS binding that were attenuated by the δ-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 δ-opioid compounds were evaluated for their agonist activity in this assay. These data suggested that differences between peptidic and nonpeptidic δ-opioid agonists in behavioral studies were most likely caused by differences in agonist efficacy. Finally, these data also revealed that [35S]GTPγS autoradiography could be used to compare efficacy differences among agonists across various brain regions in rat brain slices.",
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