The Opioid Receptor Antagonist Nalmefene Reduces Responding Maintained by Ethanol Presentation: Preclinical Studies in Ethanol‐Preferring and Outbred Wistar Rats

Abstract

Nalmefene, the 6-methylene derivative of naltrexone, was examined after subcutaneous (s.c.) (0.0001 to 8.0 mg/kg) and oral (10 to 80.0 mg/kg) administration in ethanol (EtOH)-preferring rats whose responding (i.e., lever pressing) was maintained by the presentation of EtOH. Naltrexone (0.01 to 40 mg/kg) was used as a reference opioid antagonist. EtOH (10% v/v) and saccharin (0.025 to 0.1% w/v) solutions were concurrently available for 1 hr each day under a two-lever, fixed-ratio schedule in which four responses on one lever produced the EtOH solution and four responses on the other lever produced the saccharin solution. When basal response rates for saccharin were 10% that of EtOH, all routes of nalmefene administration reduced control levels of responding maintained by EtOH by 38 to 84%. When basal response rates for saccharin-maintained responding were 60% or 82% that of EtOH, only lower s.c. naltrexone (e.g., 0.01 to 0.025 mg/kg) and nalmefene (e.g., 0.01 to 0.10 mg/kg) doses produced a selective dose-dependent suppression of EtOH-maintained responding. Higher nalmefene (0.25 to 8.0 mg/kg) and naltrexone (1.0 to 20.0 mg/kg) doses failed to produce a dose-dependent suppression on EtOH or saccharin maintained responding. Both antagonists suppressed responding maintained by EtOH primarily during the initial 10-min period, with little additional suppression occurring across the remainder of the 60-min period. Subcutaneous nalmefene was 3200- to 6400-fold more potent than oral nalmefene, suggesting bioavailability was optimized using the s.c. route. Nalmefene (0.5 mg/kg, s.c.) treatment for 10 consecutive days produced mild tolerance development, whose effects dissipated by day 8. Naltrexone (10 to 40 mg/kg) and nalmefene (1.5 to 3.0 mg/kg), given 8 to 24 hr before the test session, reduced control levels of responding maintained by EtOH by 82%. Thus, immediate opioid receptor occupancy was not required to observe antagonism. These data demonstrate that, under a variety of experimental conditions, nalmefene is an effective antagonist of responding maintained by EtOH and lend support to clinical reports that nalmefene may function as an alternative pharmacotherapy to naltrexone to reduce EtOH-motivated behavior and prevent relapse.

Opioid-Dependent Anticipatory Negative Contrast and Binge-Like Eating in Rats with Limited Access to Highly Preferred Food

“…This pretreatment interval was chosen to ensure full antagonist activity throughout the presentation of both feeders. Previous reports indicate that it takes 15-20 min for the maximum effect of subcutaneous nalmefene to be observed in the rat, with comparable functional activity and ex vivo receptor occupancy maintained for at least 1 h (June et al, 1998;Unterwald et al, 1997;Landymore et al, 1992). Treatments were given to the rats described in hypothesis 1 using a full Latin square design with 1 to 3 intervening treatment-free test days from days 24 to 37 following three daily acclimating saline injections.…”

Central Opioid Receptors Differentially Regulate the Nalmefene-Induced Suppression of Ethanol- and Saccharin-Reinforced Behaviors in Alcohol-Preferring (P) Rats

“…While a variety of neuronal systems have been shown to play a role in regulating EtOH-seeking behavior (McBride and Li, 1998;McBride et al, 1993) few have been linked as closely to the positive reinforcing properties of EtOH as the endogenous opioid systems (for a review, see Froehlich and Li, 1993;Herz, 1997;Reid and Hubbell, 1992). This conclusion is supported by pharmacological studies showing that selective (eg d and m) and nonselective (eg naloxone, naltrexone, nalmefene) opioid antagonists can decrease EtOH-seeking behaviors in a variety of preclinical animals models, suggesting that the endogenous opioid systems mediate in part, EtOH-reward processes (Herz, 1997;June et al, 1999;June et al, 1998;Krishnan-Sarin et al, 1995a). Similarly, it is also well established that the nonselective opioid antagonists naltrexone and nalmefene attenuate alcohol drinking behavior, control craving, and prevent relapse in alcohol-dependent humans (O'Malley et al, 1992;Volpicelli et al, 1992;Mason et al, 1994Mason et al, , 1999 albeit, the effectiveness of these agents has been limited by problems with compliance (Volpicelli et al, 1997;Johnson and Ait-Daoud, 2000;Kranzler, 2000).…”

“…EtOH (10% v/v) and saccharin solutions (0.05% g/v) were prepared for the operant chamber as previously described (June et al, 1998. Nalmefene, [17-N-cyclopropylmethyl-3,14b-dihydroxy-4,5a-epoxy-6-methylene-morphinan hydrochloride], the 6-methylene derivative of naltrexone was donated as a gift by IVAX Pharmaceuticals (Miami, FL).…”

“…Some researchers have argued that while both EtOH and other palatable reinforcers are affected by opioid antagonists, the relative magnitude of suppression is far less for water, sucrose, and saccharin solutions (see June et al, 1998June et al, , 1999Heyser et al, 1999). Still others contend that because the endogenous opioid systems mediate natural reinforcers (ie hunger, thirst, sex, etc) it is not realistic to expect a complete separation between EtOH intake and intake of other palatable reinforcers (Herz, 1997).…”

Prolonged Central μ-Opioid Receptor Occupancy after Single and Repeated Nalmefene Dosing

“…Nalmefene reduces alcohol drinking in preclinical models (June et al, 1998;June et al, 2004). Recent findings indicate that nalmefene and naltrexone are equally effective in reducing subjective responses to alcohol in alcoholics (Drobes et al, 2004), and in clinical studies, nalmefene has been associated with significant decreases vs placebo in reducing relapse to heavy drinking (Mason et al, 1994;Mason et al, 1999).…”