BEHAVIORAL-EFFECTS OF 6-METHYLENE NALTREXONE (NALMEFENE) IN RHESUS-MONKEYS

Nalmefene eta-dihydroxy-4,5-alpha-epoxy-6-methylenemorphinan hydrochlo ride (also NIH 10365)], a 6-methylene derivative of naltrexone, was co mpared to naltrexone for its behavioral effects in rhesus monkeys. Nal mefene had opioid antagonist actions under all conditions, having a po tency similar to that of naltrexone. In morphine-treated monkeys, disc riminating between 0.01 mg/kg of naltrexone and saline, nalmefene subs tituted completely for naltrexone at doses larger than 0.001 mg/kg. Th e onset of discriminative stimulus effects was similar for nalmefene a nd naltrexone. A dose of 0.032 mg/kg of either antagonist occasioned g reater than or equal to 90% naltrexone-lever responding beginning 6 to 8 min after s.c. administration; the effects of this dose of either a ntagonist persisted for more than 1 hr. Like the parent compound naltr exone, nalmefene also antagonized the discriminative stimulus effects of opioid agonists. Nalmefene prevented the discriminative stimulus ef fects of morphine in monkeys acutely deprived of morphine and antagoni zed the discriminative stimulus effects of nalbuphine in a separate gr oup of monkeys discriminating between nalbuphine and saline. At the do se of naltrexone and nalmefene that produced an equivalent antagonism of morphine when the antagonist was administered 0.25 hr before morphi ne (0.01 mg/kg), the duration of antagonist action was < 4 hr and > 6 hr, respectively. Nalmefene also attenuated the antinociceptive effect s of the mu agonist alfentanil and the kappa agonist Cl-977 l)1-oxaspi ro[4,5]dec-8-yl]-4-benzofuranacetamide], being 55 times more potent in attenuating the antinociceptive effects of alfentanil as compared to Cl-977. Apparent affinity (pA(2)) estimates for nalmefene in antagoniz ing the discriminative stimulus and antinociceptive effects of mu agon ists varied from 8.16 to 8.45 and the apparent affinity estimate for a ntagonizing antinociceptive effects of Cl-977 was 6.54. These results provide a quantitative comparison between nalmefene and naltrexone and generally support previous suggestions regarding the potency, duratio n of action and selectivity of nalmefene. The longer duration of actio n and greater selectivity for mu over kappa receptors observed for nal mefene, as compared to other antagonists approved for use in humans, s uggest that nalmefene might be indicated for use in opioid overdose an d in the treatment of opioid and other drug abuse.