期刊
ACS CHEMICAL NEUROSCIENCE
卷 6, 期 10, 页码 1751-1758出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.5b00113
关键词
kappa opioid receptor; U-50488; peripheral; conorphin-1; analgesia; pain
资金
- Australian Postgraduate Award
- Australian Future Fellowship [FT130101215]
- NHMRC Fellowships
- NHMRC Program Grant
- Ramaciotti Foundation Establishment Grant
- Australian Research Council [FT130101215] Funding Source: Australian Research Council
Selective activation of peripheral kappa 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 Na(v)1.8 and Na(v)1.7. Our study suggests that targeting the KOR in peripheral sensory nerve endings innervating the skin is not an alternative analgesic approach.
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