Nalmefene [17-N-cyclopropylmethyl-3,14-β-dihydroxy-4,5-α-epoxy-6- methylenemorphinan hydrochloride (also NIH 10365)], a 6-methylene derivative of naltrexone, was compared to naltrexone for its behavioral effects in rhesus monkeys. Nalmefene had opioid antagonist actions under all conditions, having a potency similar to that of naltrexone. In morphine-treated monkeys, discriminating between 0.01 mg/kg of naltrexone and saline, nalmefene substituted completely for naltrexone at doses larger than 0.001 mg/kg. The onset of discriminative stimulus effects was similar for nalmefene and naltrexone. A dose of 0.032 mg/kg of either antagonist occasioned ≥90% naltrexone-lever responding beginning 6 to 8 min after s.c. administration; the effects of this dose of either antagonist persisted for more than 1 hr. Like the parent compound naltrexone, nalmefene also antagonized the discriminative stimulus effects of opioid agonists. Nalmefene prevented the discriminative stimulus effects of morphine in monkeys acutely deprived of morphine and antagonized the discriminative stimulus effects of nalbuphine in a separate group of monkeys discriminating between nalbuphine and saline. At the dose of naltrexone and nalmefene that produced an equivalent antagonism of morphine when the antagonist was administered 0.25 hr before morphine (0.01 mg/kg), the duration of antagonist action was < 4 hr and > 6 hr, respectively. Nalmefene also attenuated the antinociceptive effects of the mu agonist alfentanil and the kappa agonist CI-977 [5R-(5,7,8-β)-N-methyl-N- [7-(1-pyrrolidinyl)1-oxaspiro[4,5]dec-8-yl]-4-benzofuranacetamide], being 55 times more potent in attenuating the antinociceptive effects of alfentanil as compared to CI-977. Apparent affinity (pA2) estimates for nalmefene in antagonizing the discriminative stimulus and antinociceptive effects of mu agonists varied from 8.16 to 8.45 and the apparent affinity estimate for antagonizing antinociceptive effects of CI-977 was 6.54. These results provide a quantitative comparison between nalmefene and naltrexone and generally support previous suggestions regarding the potency, duration of action and selectivity of nalmefene. The longer duration of action and greater selectivity for mu over kappa receptors observed for nalmefene, as compared to other antagonists approved for use in humans, suggest that nalmefene might be indicated for use in opioid overdose and in the treatment of opioid and other drug abuse.
|Original language||English (US)|
|Number of pages||8|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - Jan 1 1994|
ASJC Scopus subject areas
- Molecular Medicine