RT Journal Article SR Electronic T1 Allosterism within δ Opioid–κ Opioid Receptor Heteromers in Peripheral Sensory Neurons: Regulation of κ Opioid Agonist Efficacy JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 376 OP 386 DO 10.1124/mol.117.109975 VO 93 IS 4 A1 Blaine A. Jacobs A1 Miryam M. Pando A1 Elaine Jennings A1 Teresa A. Chavera A1 William P. Clarke A1 Kelly A. Berg YR 2018 UL http://molpharm.aspetjournals.org/content/93/4/376.abstract AB There is abundant evidence for formation of G protein-coupled receptor heteromers in heterologous expression systems, but little is known of the function of heteromers in native systems. Heteromers of δ and κ opioid receptors (DOR-KOR heteromers) have been identified in native systems. We previously reported that activation of DOR-KOR heteromers expressed by rat pain-sensing neurons (nociceptors) produces robust, peripherally mediated antinociception. Moreover, DOR agonist potency and efficacy is regulated by KOR antagonists via allosteric interactions within the DOR-KOR heteromer in a ligand-dependent manner. Here we assessed the reciprocal regulation of KOR agonist function by DOR antagonists in adult rat nociceptors in culture and in a behavioral assay of nociception. Naltrindole enhanced the potency of the KOR agonist 2-(3,4-dichlorophenyl)-N-methyl-N-[(1S)-1-phenyl-2-pyrrolidin-1-ylethyl]acetamide (ICI-199441) 10- to 20-fold, but did not alter responses to 2-(3,4-dichlorophenyl)-N-methyl-N-[(1R,2R)-2-pyrrolidin-1-ylcyclohexyl]acetamide (U50488). By contrast, the potency of U50488 was enhanced 20-fold by 7-benzylidenenaltrexone. The efficacy of 6ʹ-guanidinonaltrindole (6ʹ-GNTI) to inhibit nociceptors was blocked by small interfering RNA knockdown of DOR or KOR. Replacing 6ʹ-GNTI occupancy of DOR with either naltrindole or 7-benzylidenenaltrexone abolished 6ʹ-GNTI efficacy. Further, peptides derived from DOR transmembrane segment 1 fused to the cell membrane–penetrating HIV transactivator of transcription peptide also blocked 6ʹ-GNTI–mediated responses ex vivo and in vivo, suggesting that 6ʹ-GNTI efficacy in nociceptors is due to its positive allosteric regulation of KOR via occupancy of DOR in a DOR-KOR heteromer. Together, these results provide evidence for the existence of functional DOR-KOR heteromers in rat peripheral sensory neurons and that reciprocal, ligand-dependent allosteric interactions occur between the DOR and KOR protomers.