Interactions between morphine and the morphine-glucuronides measured by conditioned place preference and locomotor activity.
After intake of heroin or morphine, active metabolites are formed in the body. The two most important morphine metabolites are morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G). M6G and M3G are present for longer time periods and in higher concentrations than the parent drug, but their potential contribution to reward and to development of dependence and addiction is not clear. We tested the effects of morphine and M6G separately (doses of 10, 20, 30 and 50 micromol/kg), administered together, and also in combination with with 200 microm l/kg M3G in male C57BL/6J-Bom mice. M3G in doses of 50, 100, 200, 300 and 400 micromol/kg were also tested alone. We evaluated the rewarding effects in a conditioning place preference (CPP) model and the psychomotor stimulating effects by recording locomotor activity. Mice were subjected to three consecutive conditioning days with drugs or saline before testing. Changes in locomotor activity from conditioning day one to day three were also compared to the expression of CPP on the test day. This study revealed that coadministration of morphine and M6G induced CPP of similar magnitude to the sum of equimolar doses of these compounds alone, and different ratios of the two drugs did not affect the results. M3G did not cause CPP and reduced the CPP induced by both morphine and M6G when coadministered with these drugs. Morphine induced locomotor activity was reduced by coadministration of M3G, but this was not seen when M3G was co-injected with M6G. The changes in locomotor activity during the conditioning periods did not correlated with the expression of CPP. This study revealed that the morphine-glucuronides in different and complex ways can influence the pharmacological effects of psychomotor activation and reward observed after intake of morphine.
Norwegian Institute of Public Health, Division of Forensic Toxicology and Drug Abuse, P.O. Box 4404, Nydalen, 0403 Oslo, Norway. vigdis.vindenes@fhi.no
Vigdis
V
Vindenes
Ase
A
Ripel
Marte
M
Handal
Fernando
F
Boix
Jørg
J
Mørland
D000818:Animals; D003213:Conditioning, Psychological / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D009022:Morphine Derivatives / Q000008:administration & dosage* / Q000493:pharmacokinetics; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D012201:Reward; D019966:Substance-Related Disorders / Q000209:etiology / Q000503:physiopathology / Q000523:psychology; D013997:Time Factors
D009022:Morphine Derivatives; C035349:morphine-6-glucuronide; D009020:Morphine; C018108:morphine-3-glucuronide