title: The δ opioid receptor agonist SNC80 selectively activates heteromeric μ-δ opioid receptors.
abstract: Coexpressed and colocalized μ- and δ-opioid receptors have been established to exist as heteromers in cultured cells and in vivo. However the biological significance of opioid receptor heteromer activation is less clear. To explore this significance, the efficacy of selective activation of opioid receptors by SNC80 was assessed in vitro in cells singly and coexpressing opioid receptors using a chimeric G-protein-mediated calcium fluorescence assay, SNC80 produced a substantially more robust response in cells expressing μ-δ heteromers than in all other cell lines. Intrathecal SNC80 administration in μ- and δ-opioid receptor knockout mice produced diminished antinociceptive activity compared with wild type. The combined in vivo and in vitro results suggest that SNC80 selectively activates μ-δ heteromers to produce maximal antinociception. These data contrast with the current view that SNC80 selectively activates δ-opioid receptor homomers to produce antinociception. Thus, the data suggest that heteromeric μ-δ receptors should be considered as a target when SNC80 is employed as a pharmacological tool in vivo.
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota College of Pharmacy, Minneapolis, Minnesota, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Metcalf
authors.forename: Ajay S
authors.initials: AS
authors.lastname: Yekkirala
authors.forename: Michael D
authors.initials: MD
authors.lastname: Powers
authors.forename: Kelley F
authors.initials: KF
authors.lastname: Kitto
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Fairbanks
authors.forename: George L
authors.initials: GL
authors.lastname: Wilcox
authors.forename: Philip S
authors.initials: PS
authors.lastname: Portoghese
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000378:metabolism*
chemical_list: D000701:Analgesics, Opioid; D001549:Benzamides; D010879:Piperazines; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide