QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.108.143925v1 328/1/193    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ko, M.-C. Articles by Husbands, S. M. Search for Related Content PubMed PubMed Citation Articles by Ko, M.-C. Articles by Husbands, S. M.

BEHAVIORAL PHARMACOLOGY

Effects of Atypical -Opioid Receptor Agonists on Intrathecal Morphine-Induced Itch and Analgesia in Primates

Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan (M.-C.K.); Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom (S.M.H.); and Department of Psychology, Institute of Neuroscience, and Research Center for Mind, Brain, and Learning, National Cheng Chi University, Taipei, Taiwan (M.-C.K.)

Itch/pruritus is the most common side effect associated with spinal administration of morphine given to humans for analgesia. The aim of this study was to investigate the effectiveness of -opioid receptor (KOR) agonists with diverse chemical structures as antipruritics and to elucidate the receptor mechanism underlying the antipruritic effect in monkeys. In particular, previously proposed non-KOR-1 agonists, including nalfurafine [TRK-820, 17-cyclopropylmethyl-3,14β-dihydroxy-4,5-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan], bremazocine [(±)-6-ethyl-1,2,3,4,5,6-hexahydro-3-[(1-hydroxycyclopropy)-methyl]-11,11-dimethyl-2,6-methano-3-benzazocin-8-ol], and GR 89696 [4-[(3,4-dichlorophenyl)acetyl]-3-(1-pyrrolidinylmethyl)-1-piperazinecarboxylic acid methyl ester] were studied in various behavioral assays for measuring itch/scratching, analgesia, and respiratory depression. Systemic administration of nalfurafine (0.1–1 µg/kg), bremazocine (0.1–1 µg/kg), or GR 89696 (0.01–0.1 µg/kg) dose-dependently attenuated intrathecal morphine (0.03 mg)-induced scratching responses without affecting morphine antinociception. The combination of intrathecal morphine with these KOR agonists did not cause sedation. In addition, pretreatment with effective antiscratching doses of nalfurafine, bremazocine, or GR 89696 did not antagonize systemic morphine-induced antinociception and respiratory depression. The dose-addition analysis revealed that there is no subadditivity for nalfurafine in combination with morphine in the antinociceptive effect. Furthermore, the KOR antagonist study revealed that antiscratching effects of both nalfurafine and a prototypical KOR-1 agonist, U-50488H [trans-(±)-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]-cyclohexyl)-benzeneacetamide], could be blocked completely by a selective KOR antagonist, nor-binaltorphimine (3 mg/kg). These findings suggest that the agonist action on KOR mainly contributes to the effectiveness of these atypical KOR agonists as antipruritics, and there is no evidence for KOR subtypes or µ-opioid antagonist action underlying the effects of these KOR agonists. This mechanism-based study further supports the clinical potential of KOR agonists as antipruritics under the context of spinal opioid analgesia.

Address correspondence to: Dr. Mei-Chuan Ko, Department of Pharmacology, University of Michigan Medical School, 1301 MSRB III, Ann Arbor, MI 48109-5632. E-mail: mko{at}umich.edu