In vivo characterization of the opioid antagonist nalmefene in mice.
OBJECTIVE
The current study assessed the in vivo antagonist properties of nalmefene using procedures previously used to characterize the opioid antagonists naloxone, naltrexone, 6beta-naltrexol and nalbuphine.


METHODS
ICR mice were used to generate antagonist dose-response curves with intraperitoneal (i.p.) nalmefene against fixed A(90) doses of morphine in models of morphine-stimulated hyperlocomotion and antinociception. Additional dose-response curves for antagonist precipitated opioid withdrawal were run in mice treated acutely (100mg/kg, s.c., -4h) or chronically (75mg pellet, s.c., -72h) with morphine. Comparisons were made between antagonist potency and degree of precipitated withdrawal.


RESULTS
Nalmefene produced dose- and time-related antagonism of morphine-induced increases in locomotor activity with a calculated ID(50) (and 95% confidence interval) of 0.014 (0.007-0.027)mg/kg. Nalmefene produced rapid reversal of morphine-induced locomotor activity (5.1min for 50% reduction in morphine effect). A 0.32mg/kg dose of nalmefene produced blockade of morphine-induced antinociception in the 55 degrees C tail-flick test that lasted approximately 2h. Nalmefene was able to potently precipitate withdrawal in mice treated acutely or chronically with morphine.


CONCLUSIONS
These results demonstrate that nalmefene is similar to naloxone and naltrexone with respect to its in vivo pharmacology in mice. Specifically, nalmefene produces potent antagonism of morphine agonist effects while precipitating severe withdrawal. The compound has a slower onset and longer duration of action compared to naloxone and naltrexone. The data allows for a more complete preclinical comparison of nalmefene against other opioid antagonists including the putative opioid neutral antagonist 6beta-naltrexol.
Osborn
Melissa D
MD
Department of Nurse Anesthesia, Westbrook College of Health Professions, University of New England, Portland, ME 04103, United States.
Lowery
John J
JJ
Skorput
Alex G J
AG
Giuvelis
Denise
D
Bilsky
Edward J
EJ
D000701:Analgesics, Opioid / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009020:Morphine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D009271:Naltrexone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D010146:Pain / Q000188:drug therapy; D013375:Substance Withdrawal Syndrome; D013997:Time Factors
D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D009271:Naltrexone; D009020:Morphine; C038981:nalmefene