Behavioural sensitization in mice induced by morphine-glucuronide metabolites.
Sensitization is thought to be involved in central aspects of drug addiction. Both morphine-3-glucuronid (M3G) and morphine-6-glucuronid (M6G) are rapidly formed in high concentrations shortly after heroin and morphine consumption. Their role in the development of sensitization has not previously been studied. In our study, mice received three injections of M6G or morphine at six day intervals. M6G induced locomotor sensitization comparable to morphine as early as the first injection. In a second experiment two injections of M6G or morphine were given, separated by 6, 12, 18, 24 or 30 days. A sensitized response was observed for both morphine and M6G up to 18 days after the first injection. In a third experiment with two injections, the first with M6G and the second with morphine, or the opposite sequence, M6G did not induce cross-sensitization to morphine although morphine induced cross-sensitization to M6G. Finally, pretreatment with M3G induced sensitization of morphine locomotor activity but not M6G. In conclusion M6G induced long-lasting sensitization similar but not identical to morphine. M3G was shown to sensitize morphine induced locomotor activity in a similar way to morphine pretreatment. This suggests that morphine-glucuronide metabolites may play a role in the development of addiction to morphine.
Handal
Marte
M
Norwegian Institute of Public Health, Division of Forensic Toxicology and Drug Abuse, P.O. Box 4404 Nydalen, NO-0403 Oslo, Norway. marte.handal@fhi.no
Ripel
Ase
A
Skurtveit
Svetlana
S
Mørland
Jørg
J
D000701:Analgesics, Opioid / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009022:Morphine Derivatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects
D000701:Analgesics, Opioid; D009022:Morphine Derivatives; C035349:morphine-6-glucuronide; C018108:morphine-3-glucuronide