title: Activation of κ Opioid Receptors in Cutaneous Nerve Endings by Conorphin-1, a Novel Subtype-Selective Conopeptide, Does Not Mediate Peripheral Analgesia.
abstract: Selective activation of peripheral κ opioid receptors (KORs) may overcome the dose-limiting adverse effects of conventional opioid analgesics. We recently developed a vicinal disulfide-stabilized class of peptides with subnanomolar potency at the KOR. The aim of this study was to assess the analgesic effects of one of these peptides, named conorphin-1, in comparison with the prototypical KOR-selective small molecule agonist U-50488, in several rodent pain models. Surprisingly, neither conorphin-1 nor U-50488 were analgesic when delivered peripherally by intraplantar injection at local concentrations expected to fully activate the KOR at cutaneous nerve endings. While U-50488 was analgesic when delivered at high local concentrations, this effect could not be reversed by coadministration with the selective KOR antagonist ML190 or the nonselective opioid antagonist naloxone. Instead, U-50488 likely mediated its peripheral analgesic effect through nonselective inhibition of voltage-gated sodium channels, including peripheral sensory neuron isoforms NaV1.8 and NaV1.7. Our study suggests that targeting the KOR in peripheral sensory nerve endings innervating the skin is not an alternative analgesic approach.
authors.affiliation: School of Pharmacy, University of Queensland , Woolloongabba, QLD 4102, Australia.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Deuis
authors.affiliation: School of Pharmacy, University of Queensland , Woolloongabba, QLD 4102, Australia.
authors.forename: Ella
authors.initials: E
authors.lastname: Whately
authors.forename: Andreas
authors.initials: A
authors.lastname: Brust
authors.affiliation: School of Pharmacy, University of Queensland , Woolloongabba, QLD 4102, Australia.
authors.forename: Marco C
authors.initials: MC
authors.lastname: Inserra
authors.affiliation: School of Pharmacy, University of Queensland , Woolloongabba, QLD 4102, Australia.
authors.forename: Naghmeh H
authors.initials: NH
authors.lastname: Asvadi
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Lewis
authors.forename: Paul F
authors.initials: PF
authors.lastname: Alewood
authors.affiliation: School of Pharmacy, University of Queensland , Woolloongabba, QLD 4102, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Cabot
authors.affiliation: School of Pharmacy, University of Queensland , Woolloongabba, QLD 4102, Australia.
authors.forename: Irina
authors.initials: I
authors.lastname: Vetter
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000627:therapeutic use; D000700:Analgesics / Q000627:therapeutic use; D018712:Analgesics, Non-Narcotic / Q000627:therapeutic use; D000818:Animals; D002351:Carrageenan / Q000633:toxicity; D002945:Cisplatin / Q000633:toxicity; D004195:Disease Models, Animal; D005620:Freund's Adjuvant / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000150:complications / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009270:Naloxone / Q000494:pharmacology / Q000627:therapeutic use; D009411:Nerve Endings / Q000187:drug effects / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology*; D010147:Pain Measurement; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000188:drug therapy; D051381:Rats; D017208:Rats, Wistar; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000378:metabolism*; D012867:Skin / Q000294:innervation*
chemical_list: D000700:Analgesics; D018712:Analgesics, Non-Narcotic; D009842:Oligopeptides; D010455:Peptides; D017473:Receptors, Opioid, kappa; C000609412:conorphin-1 peptide; D009270:Naloxone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D002351:Carrageenan; D005620:Freund's Adjuvant; D002945:Cisplatin
keywords: U-50488; analgesia; conorphin-1; pain; peripheral; κ opioid receptor