Morphine-6beta-glucuronide rapidly increases pain sensitivity independently of opioid receptor activity in mice and humans.
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.
van Dorp
Eveline L A
EL
Leiden University Medical Center, Leiden, The Netherlands.
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
D000293:Adolescent; D000328:Adult; D000818:Animals; D016291:Dizocilpine Maleate / Q000494:pharmacology; D005260:Female; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009022:Morphine Derivatives / Q000494:pharmacology*; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D011930:Reaction Time / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D011957:Receptors, Opioid / Q000187:drug effects*; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000235:genetics; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000235:genetics; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000235:genetics; D055815:Young Adult
D009022:Morphine Derivatives; D009292:Narcotic Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D009270:Naloxone; D009271:Naltrexone; C035349:morphine-6-glucuronide; D016291:Dizocilpine Maleate