Morphine-6-glucuronide-induced locomotor stimulation in mice: role of opioid receptors.
Morphine-6beta-glucuronide is a major metabolite of morphine with potent analgesic actions. To explore the importance of this opiate when administered as a drug by its own or in morphine action, we studied the locomotor activity response to morphine and morphine-6-glucuronide in drug-naive C57 BL/6JBom mice. The effects of administration of the two opiates on a battery of 7 different locomotor activities were studied and compared to saline controls. A dose of 20 micromol/kg morphine-6-glucuronide resulted in more locomotion than the same dose of morphine, while at higher doses (up to 120 micromol/kg), similar increases for most locomotor behaviours were recorded for both drugs. Pretreatment with naltrindole indicated that the delta-receptors play an equivalent but minor role in mediating both morphine-6-glucuronide and morphine hyperlocomotion. Administration of high naltrexone doses (10 mg/kg) completely abolished the locomotor stimulation induced by both opiates. However, at intermediate naltrexone doses of 0.25 and 0.5 mg/kg, morphine-induced behaviours was completely inhibited while morphine-6-glucuronide induced behaviours demonstrated partial resistance to naltrexone inhibition. The mu1-specific receptor antagonist naloxonazine caused 75% reduction of morphine induced behaviours and only 50% inhibition of morphine-6-glucuronide induced behaviors. Taken together our observations indicated general similarity but also marked differences between morphine and morphine-6-glucuronide with respect to opiate receptors mediating the locomotor stimulatory effect.
Grung
M
M
National Institute of Forensic Toxicology, Oslo, Norway.
Skurtveit
S
S
Aasmundstad
T A
TA
Handal
M
M
Alkana
R L
RL
Mørland
J
J
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D009022:Morphine Derivatives / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects*; D009270:Naloxone / Q000031:analogs & derivatives / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D011957:Receptors, Opioid / Q000187:drug effects* / Q000378:metabolism
D000701:Analgesics, Opioid; D009022:Morphine Derivatives; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D009270:Naloxone; D009271:Naltrexone; C035349:morphine-6-glucuronide; D009020:Morphine; C034643:naloxonazine; C055382:naltrindole