Nalmefene Induced Elevation in Serum Prolactin in Normal Human Volunteers: Partial Kappa Opioid Agonist Activity?

Bart, Gavin; Schluger, James H.; Borg, Lisa; Ho, Ann; Bidlack, Jean M.; Kreek, Mary Jeanne

doi:10.1038/sj.npp.1300811

Cited by 126 publications

(94 citation statements)

References 66 publications

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“…Presumably, the profile of opioid receptor binding coupled with the drug-like properties of compound 5 contributes to the optimal functional activity as an alcohol selfadministration inhibition agent in vivo. This is in agreement with recent studies that show that an opioid with strong k-opioid receptor antagonism, albeit possessing some opioid agonism (i.e., nalmefene) (Bart et al, 2005), was more effective at inhibition of alcohol self-administration than an opioid with broad opioid receptor antagonism (i.e., naltrexone) (Walker and Koob, 2008). Consequently, compound 5 and related agents may represent exciting leads for the next generation of opioid compounds useful in the treatment of alcohol abuse.…”

Section: Potent Alcohol Cessation Agentssupporting

confidence: 78%

Potent Inhibition of Alcohol Self-Administration in Alcohol-Preferring Rats by aκ-Opioid Receptor Antagonist

Cashman

Azar

2014

J Pharmacol Exp Ther

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A substituted aryl amide derivative of 6-naltrexamine-17-cyclopropylmethyl-3,14b-dihydroxy-4,5a-epoxy-6b-[(49-trimethylfluoro) benzamido]morphinan-hydrochloride-(compound 5), previously shown to be a potent k-opioid receptor antagonist, was used to characterize the physicochemical properties and efficacy to decrease alcohol self-administration in alcohol-preferring rats (P-rats) and binge-like P-rats. Previous studies showed that compounds closely related to compound 5 possessed favorable properties regarding penetration of the blood-brain barrier. Pharmacokinetic studies showed that compound 5 had acceptable bioavailability. In contrast to other k-receptor antagonists, in particular norbinaltorphimine, compound 5 showed favorable drug-like properties. Based on these findings, further studies were done. Safety studies showed that compound 5 was not hepatotoxic at doses 200-fold greater than an efficacious dose.The effects of compound 5 or naltrexone on the hepatotoxicity of thiobenzamide were investigated. In contrast to naltrexone, which exacerbated thiobenzamide-mediated hepatotoxicity, compound 5 was observed to be hepatoprotective. Based on the physicochemical properties of compound 5, the compound was examined in rat animal models of alcohol self-administration. The inhibition of ethanol self-administration by compound 5 in alcohol-dependent and alcohol-nondependent P-rats trained to self-administer a 10% (w/v) ethanol solution, using operant techniques, showed very potent efficacy (i.e., estimated ED 50 values of 4-5 mg/kg). In a binge-like P-rat animal model, inhibition of alcohol self-administration by compound 5 had an estimated ED 50 value of 8 mg/kg. The results suggest that compound 5 is a potent drug-like k-opioid receptor antagonist of utility in alcohol cessation medications development.

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Section: Potent Alcohol Cessation Agentssupporting

confidence: 78%

Potent Inhibition of Alcohol Self-Administration in Alcohol-Preferring Rats by aκ-Opioid Receptor Antagonist

Cashman

Azar

2014

J Pharmacol Exp Ther

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“…Heroin and methadone also stimulate prolactin release in opioid-dependent men (Bart et al, 2003;Ellingboe et al, 1980;Kreek, 1978). Furthermore, mixed action mu-kappa opioids such as buprenorphine and nalmefene also increase serum prolactin levels in humans (Bart et al, 2005;Rolandi et al, 1983). These data suggest that the nalbuphine-induced increases in serum prolactin levels observed in the present study may involve interactions of the drug with both kappa and mu opioid receptors.…”

Section: Clinical Studies Of Prolactin Interactions With Kappa and Musupporting

confidence: 64%

Effects of nalbuphine on anterior pituitary and adrenal hormones and subjective responses in male cocaine abusers

Goletiani

Mendelson

Sholar

et al. 2007

Pharmacology Biochemistry and Behavior

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Nalbuphine (Nubain®) is a mixed action mu-kappa agonist used clinically for the management of pain. Nalbuphine and other mu-kappa agonists decreased cocaine self-administration in preclinical models. Cocaine stimulates the hypothalamic-pituitary-adrenal (HPA) axis, but the effects of nalbuphine on the HPA axis are unknown. Analgesic doses (5 and 10 mg/70 kg) of IV nalbuphine were administered to healthy male cocaine abusers, and plasma levels of PRL, ACTH and cortisol were measured before and at 10, 17, 19, 23, 27, 31, 35, 40, 45, 60, 75, 105, 135 min after nalbuphine administration. Subjective effects were measured on a Visual Analog Scale (VAS). Prolactin (PRL) increased significantly within 17 min (P=.04) and reached peak levels of 22.1 ± 7.1 ng/ml and 54.1 ± 11.3 at 60 min after low and high dose nalbuphine administration, respectively. VAS reports of "Sick," "Bad" and "Dizzy" were significantly higher after 10 mg/70 kg than after 5 mg/70 kg nalbuphine (P=.05−.0001), and were significantly correlated with increases in PRL (P=.05−.0003). However, sedation and emesis were observed only after a 10 mg/70 kg dose of nalbuphine. Interestingly, ACTH and cortisol levels did not change significantly after administration of either dose of nalbuphine. Taken together, these data suggest that nalbuphine had both mu-and kappa-like effects on PRL (PRL increase) but did not increase ACTH and cortisol.

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“…When a direct comparison was made between naltrexone and nalmefene on opioid receptor binding affinity, it was clearly shown that while both nalmefene and naltrexone had equipotent binding affinities for the m-opioid receptor, nalmefene had a twofold increase in potency at the k-opioid receptor compared to naltrexone (Michel et al, 1985) at low doses. The affinity of nalmefene for the k-opioid receptor has also been observed in humans (Bart et al, 2005). In the present experiment, a dose-to-dose comparison was made possible by the fact that nalmefene and naltrexone have virtually identical molecular weights (339.4 and 341.4, respectively) and pharmacokinetic profiles (Advanced Chemistry Development, 2006).…”

Section: Discussionmentioning

confidence: 95%

“…However, naltrexone, although classified as a general opioid receptor antagonist, actually has a higher affinity for the m-opioid receptor subtype than the d and k subtypes at low doses (Abbott et al, 1986;Millan, 1989;Millan et al, 1989;Walker et al, 1994;Stromberg et al, 1998). Nalmefene is also classified as a general opioid receptor antagonist and is equipotent with naltrexone at the m-opioid receptor, but unlike naltrexone, has a higher affinity for the k and d receptors in rats (Michel et al, 1985) and the k receptor in humans (Bart et al, 2005). Therefore, even at low doses, nalmefene can be considered a 'true' general opioid receptor antagonist.…”

mentioning

confidence: 99%

Pharmacological Evidence for a Motivational Role of κ-Opioid Systems in Ethanol Dependence

Walker

Koob

2007

Neuropsychopharmacol

365

376

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The purpose of this study was to test the hypothesis that activation of the dynorphin/kappa (k)-opioid system has a role in the increased consumption of ethanol in dependent animals. The effects of three opioid receptor antagonists with different effects on opioid receptors, naltrexone, nalmefene, and nor-binaltorphimine (nor-BNI), were compared in their ability to decrease ethanol self-administration in nondependent and ethanol-dependent male Wistar rats. Nalmefene and naltrexone are both opioid receptor ligands with comparable molecular weights and pharmacokinetic profiles, but differing specificity for the three opioid receptor subtypes at low doses, while nor-BNI is a selective k-opioid receptor antagonist. Dependence was induced in half the animals by subjecting them to a 4-week intermittent vapor exposure period in which animals were exposed to ethanol vapor for 14 h per day. Subsequent to dependence induction, nalmefene, naltrexone, and nor-BNI were tested for their ability to modulate self-administration of ethanol in vapor-exposed and control rats. The results indicated that both nalmefene and naltrexone induced a significant dose-dependent decrease in the number of lever presses for ethanol in both groups of animals. However, in ethanol-dependent animals, nalmefene was significantly more effective in suppressing ethanol intake than naltrexone. Nor-BNI selectively attenuated ethanol-dependent self-administration while leaving nondependent ethanol self-administration intact. Because naltrexone is primarily selective for the m-opioid receptor, and nalmefene is primarily selective for the m-and k-opioid receptor subtypes, the fact that nalmefene demonstrates more suppression in dependent animals suggests that opioid systems distinct from the m-regulated portion may be involved in the increased drinking seen during withdrawal in dependent animals. The results with nor-BNI confirm that k-opioid receptor antagonism selectively decreases dependence-induced ethanol self-administration, which supports the hypothesis that dynorphin/k-opioid systems are dysregulated in dependence and contribute to the increased drinking seen during acute withdrawal in dependent rats. INTRODUCTIONThe acute effects of ethanol have been shown to be both reinforcing and rewarding in animal models such as operant self-administration (Anderson and Thompson, 1974;Smith and Davis, 1974) and the conditioned place preference paradigm (Bozarth, 1990;Walker and Ettenberg, 2007). Ethanol produces its effects on the central nervous system via a variety of pharmacological mechanisms. These include alterations in the function of the cholinergic, dopaminergic, g-aminobutyric acid, glutamatergic, opioidergic, and serotonergic neurotransmitter systems (for review see Eckardt et al, 1998). In the case of the endogenous opioid system and its receptor subtypes (m, d, kFselective for the three main classes of endogenous opioids: b-endorphin, enkephalins, and dynorphins, respectively), acute ethanol has been shown to stimulate the release of b-endorphin...

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Nalmefene Induced Elevation in Serum Prolactin in Normal Human Volunteers: Partial Kappa Opioid Agonist Activity?

Cited by 126 publications

References 66 publications

Potent Inhibition of Alcohol Self-Administration in Alcohol-Preferring Rats by aκ-Opioid Receptor Antagonist

Potent Inhibition of Alcohol Self-Administration in Alcohol-Preferring Rats by aκ-Opioid Receptor Antagonist

Effects of nalbuphine on anterior pituitary and adrenal hormones and subjective responses in male cocaine abusers

Pharmacological Evidence for a Motivational Role of κ-Opioid Systems in Ethanol Dependence

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