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

M. C.Holden Ko, Heeseung Lee, Michael S. Song, Katarzyna Sobczyk-Kojiro, Henry I. Mosberg, Shiroh Kishioka, James H. Woods, Norah N. Naughton

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100 Scopus citations


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. κ-Opioid agonists possess several actions that are opposite to μ-opioid agonists. We proposed to investigate the role of κ-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°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 μg) -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 agonistinduced pruritus.

Original languageEnglish
Pages (from-to)173-179
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number1
StatePublished - 1 Apr 2003


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