title: Activation of kappa-opioid receptors inhibits pruritus evoked by subcutaneous or intrathecal administration of morphine in monkeys.
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. 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.
authors.affiliation: Department of Pharmacology, Division of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109-0632, USA. mko@umich.edu
authors.forename: M C Holden
authors.initials: MC
authors.lastname: Ko
authors.forename: Heeseung
authors.initials: H
authors.lastname: Lee
authors.forename: Michael S
authors.initials: MS
authors.lastname: Song
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Sobczyk-Kojiro
authors.forename: Henry I
authors.initials: HI
authors.lastname: Mosberg
authors.forename: Shiroh
authors.initials: S
authors.lastname: Kishioka
authors.forename: James H
authors.initials: JH
authors.lastname: Woods
authors.forename: Norah N
authors.initials: NN
authors.lastname: Naughton
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D004347:Drug Interactions; D005260:Female; D007278:Injections, Spinal; D007279:Injections, Subcutaneous; D008253:Macaca mulatta; D008297:Male; D009020:Morphine / Q000009:adverse effects*; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D011537:Pruritus / Q000139:chemically induced / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000378:metabolism*
chemical_list: D018712:Analgesics, Non-Narcotic; D009292:Narcotic Antagonists; D017473:Receptors, Opioid, kappa; C051844:norbinaltorphimine; D009271:Naltrexone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D009020:Morphine