Morphine-6beta-glucuronide rapidly increases pain sensitivity independently of opioid receptor activity in mice and humans.

Full Abstract

BACKGROUND: Previous data indicate that morphine-6beta-glucuronide (M6G), a morphine metabolite with analgesic properties, can paradoxically increase pain sensitivity in mice and humans. The authors tested mice and humans for M6G hyperalgesia and assessed the contribution of N-methyl-D-aspartate receptor activity in mice. METHODS: Nociception after acute injection (10 mg/kg) and chronic infusion (1.6 mg/kg per 24 h) of M6G or saline was assayed using the tail-withdrawal test in CD-1 mice implanted with pellets containing the opioid antagonist naltrexone or placebo and in knockout mice lacking mu-, kappa-, and delta-opioid receptors and their B6129F(1) controls. In volunteers, responses to heat pain were tested after a M6G (0.4 mg/kg) injection in the presence of a continuous high naloxone (0.04-mg/kg bolus followed by 0.04 mg/kg per hour) or saline background infusion. RESULTS: Acute M6G injection evoked analgesia in CD-1 mice implanted with placebo pellets and B6129F(1) control mice, whereas it caused hyperalgesia in CD-1 mice treated concurrently with naltrexone and in knockout mice. Continuous M6G infusion produced hyperalgesia within 24 h, lasting for a minimum of 6 days, in both placebo- and naltrexone-pelleted mice. The N-methyl-D-aspartate receptor antagonist MK-801 (0.05 mg/kg) blocked and reversed hyperalgesia after the acute injection and continuous infusion of M6G, respectively. In humans, M6G increased heat pain sensitivity for at least 6 h independently of simultaneous naloxone infusion. CONCLUSIONS: These data indicate that M6G causes hyperalgesia independent of previous or concurrent opioid receptor activity or analgesia. In mice, a causal role for the N-methyl-D-aspartate receptor is also indicated.

Author information

Author/s: van Dorp, Eveline L A (EL); Kest, Benjamin (B); Kowalczyk, William J (WJ); Morariu, Aurora M (AM); Waxman, Amanda R (AR); Arout, Caroline A (CA); Dahan, Albert (A); Sarton, Elise Y (EY);

Affiliation: Leiden University Medical Center, Leiden, The Netherlands.

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: Anesthesiology (Anesthesiology), published in United States. (Language: eng)

Reference: 2009-Jun; vol 110 (issue 6) : pp 1356-63

Dates: Created 2009/05/22; Completed 2009/06/16;

PMID: 19461298, status: MEDLINE (last retrieval date: 6/16/2009, IMS Date: 16 Jun 2009 00:00:00)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

Comments and Corrections

CommentIn: Anesthesiology. 2009 Jun;110(6):1209-10. (PMID: 19417609)

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Associated Chemicals: Morphine Derivatives (0) ; Narcotic Antagonists (0) ; Receptors, N-Methyl-D-Aspartate (0) ; Receptors, Opioid (0) ; Receptors, Opioid, delta (0) ; Receptors, Opioid, kappa (0) ; Receptors, Opioid, mu (0) ; Naltrexone (16590-41-3) ; morphine-6-glucuronide (20290-10-2) ; Naloxone (465-65-6) ; Dizocilpine Maleate (77086-22-7)

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