Abstract
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 oftrans-(±)-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 agonist-induced pruritus.
Footnotes
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This study was supported by U.S. Public Health Service Grant DA-13685 (to M.C.H.K.). Preliminary results were presented at the joint meeting of American Society for Biochemistry and Molecular Biology and American Society for Pharmacology and Experimental Therapeutics, Boston, MA, June 4 to 8, 2000 (FASEB J14:A1318).
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DOI: 10.1124/jpet.102.044909
- Abbreviations:
- MOR
- μ-opioid receptor
- KOR
- κ-opioid receptor
- nor-BNI
- nor-binaltorphimine
- MPE
- maximum possible effect
- U-50488H
- trans-(±)-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]-cyclohexyl)-benzeneacetamide
- Received September 25, 2002.
- Accepted December 30, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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