Activation of k opioid receptors in cutaneous nerve endings by conorphin-1, a novel subtype-selective conopeptide, does not mediate peripheral analgesia

Deuis, Jennifer, Whately, Ella, Brust, Andreas, Inserra, Marco, Asvadi, Naghmeh Hajarol, Lewis, Richard J., Alewood, Paul F., Cabot, Peter J. and Vetter, Irina (2015) Activation of k opioid receptors in cutaneous nerve endings by conorphin-1, a novel subtype-selective conopeptide, does not mediate peripheral analgesia. ACS Chemical Neuroscience, 6 10: 1751-1758. doi:10.1021/acschemneuro.5b00113


Author Deuis, Jennifer
Whately, Ella
Brust, Andreas
Inserra, Marco
Asvadi, Naghmeh Hajarol
Lewis, Richard J.
Alewood, Paul F.
Cabot, Peter J.
Vetter, Irina
Title Activation of k opioid receptors in cutaneous nerve endings by conorphin-1, a novel subtype-selective conopeptide, does not mediate peripheral analgesia
Journal name ACS Chemical Neuroscience   Check publisher's open access policy
ISSN 1948-7193
Publication date 2015-10-21
Year available 2015
Sub-type Article (original research)
DOI 10.1021/acschemneuro.5b00113
Open Access Status Not Open Access
Volume 6
Issue 10
Start page 1751
End page 1758
Total pages 8
Place of publication Washington, DC United States
Publisher American Chemical Society
Language eng
Formatted 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.
Keyword κ opioid receptor
U-50488
Peripheral
Conorphin-1
Analgesia
Pain
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
Institute for Molecular Bioscience - Publications
 
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Created: Thu, 29 Oct 2015, 22:01:15 EST by Susan Allen on behalf of Institute for Molecular Bioscience