u-50488 and Peripheral-Nervous-System-Diseases

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.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Analgesics, Non-Narcotic; Animals; Carrageenan; Cisplatin; Disease Models, Animal; Freund's Adjuvant; Gene Expression Regulation; HEK293 Cells; Humans; Inflammation; Male; Mice; Mice, Inbred C57BL; Naloxone; Nerve Endings; Oligopeptides; Pain; Pain Measurement; Peptides; Peripheral Nervous System Diseases; Rats; Rats, Wistar; Receptors, Opioid, kappa; Skin

The effect of repeated contralateral administration of the kappa-opioid receptor agonist U-50,488H (trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamide methanesulfonate) on nociceptive behaviour was investigated and compared with ipsilateral and bilateral treatments in a rat model of peripheral unilateral neuropathy (chronic constriction of the common sciatic nerve). Administration of 0.3 mg U-50,488H into the contralateral hindpaw on days 6 and 10 after induction of mononeuropathy increased hindpaw withdrawal latency to mechanical but not to thermal stimulation compared to saline-treated rats. No difference in pain-related behaviour was found between different peripheral (contralateral, ipsilateral and bilateral) treatments with 0.3 mg U-50,488H. Autotomy behaviour was reduced for 6 weeks after sciatic nerve ligation in rats treated contralaterally with the opioid receptor agonist. Antinociceptive effects of contralaterally administered U-50,488H were abolished by the peripherally acting opioid receptor antagonist naloxone methiodide. Our findings indicate that contralateral treatment with U-50,488H attenuates nociceptive behaviour in mononeuropathic rats. These antinociceptive effects are mediated via peripheral opioid receptors.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Non-Narcotic; Animals; Behavior, Animal; Constriction, Pathologic; Functional Laterality; Hot Temperature; Male; Pain; Peripheral Nervous System Diseases; Physical Stimulation; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Sciatic Nerve; Self Mutilation