Activation of kappa-opioid receptors inhibits pruritus evoked by subcutaneous or intrathecal administration of morphine in monkeys

Ko, M.C.H.; Lee, H.; Song, M.S.; Sobczyk-Kojiro, K.; Mosberg, H.I.; Kishioka, S.; Woods, J.H.; Naughton, N.N.

Journal of Pharmacology and Experimental Therapeutics 305(1): 173-179


ISSN/ISBN: 0022-3565
PMID: 12649366
DOI: 10.1124/jpet.102.044909
Accession: 010120942

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Pruritus (itch sensation) is the most common side effect associated with spinal administration of morphine given to humans for analgesia. A variety of agents have been proposed as antipruritics with poorly understood mechanisms and they are effective with variable success. kappa-Opioid agonists possess several actions that are opposite to micro -opioid agonists. We proposed to investigate the role of kappa-opioid receptors (KORs) in morphine-induced scratching and antinociception in monkeys. Scratching responses were counted by observers blinded to treatment. Antinociception was measured by a warm water (50 degrees C) tail-withdrawal assay. Pretreatment with low doses of trans-(+/-)-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]-cyclohexyl)-benzeneacetamide (U-50488H) (0.032-0.18 mg/kg s.c.), a selective KOR agonist, dose dependently suppressed the s.c. morphine dose-effect curve for scratching and potentiated s.c. morphine-induced antinociception. In addition, s.c. U-50488H attenuated i.t. morphine (10 and 32 micro g)-induced scratching while maintaining or enhancing i.t. morphine-induced antinociception. The combination of s.c. or i.t. morphine with low doses of U-50488H did not cause sedation. More importantly, pretreatment with 3.2 mg/kg nor-binaltorphimine, a selective KOR antagonist, blocked the effects of s.c. U-50488H on both s.c. and i.t. morphine-induced scratching. These results indicate that activation of KOR attenuates morphine-induced scratching without interfering with antinociception in monkeys. This mechanism-based finding provides functional evidence in support of the clinical potential of KOR agonists as antipruritics in the presence of MOR agonist-induced pruritus.