Neuroendocrine effects of naltrexone versus nalmefene in humans

Abstract

Objective Naltrexone and nalmefene are approved for the treatment of alcohol use disorders, in different countries. Naltrexone is also approved for the treatment for opioid use disorders, most recently in a depot formulation. These compounds target primarily μ(mu)‐ and κ(kappa)‐opioid receptor systems, which are involved in the downstream neurobiological effects of alcohol and in the modulation of neuroendocrine stress systems. The study objective was to compare the neuroendocrine effects of naltrexone and nalmefene on adrenocorticotropic hormone (ACTH), cortisol, and prolactin, in normal volunteers. Method Adult normal volunteers (n = 11 male and n = 9 female) were studied in a stress‐minimized inpatient setting on three consecutive days, after intravenous saline, naltrexone HCl (10 mg), or nalmefene HCl (10 mg), in fixed order. ACTH, cortisol, and prolactin were analyzed pre‐injection and up to 180 min post‐injection. Results Naltrexone and nalmefene caused elevations in ACTH and cortisol compared with saline. Nalmefene had a greater effect on ACTH and cortisol, compared with naltrexone. Both compounds also caused elevations in prolactin in males (females were not examined, due to the influence of menstrual cycle on prolactin). Conclusions This study suggests that both nalmefene and naltrexone have effects potentially due to κ‐partial agonism in humans, as well as antagonist effects at μ‐receptors.

Solving an Old Puzzle: Elucidation and Evaluation of the Binding Mode of Salvinorin A at the Kappa Opioid Receptor

“…The effect of omitting moieties at C1 are contradictory. While the complete omission of substituents (18) only shows a small impact on KOR affinity and activity [43,78], the change of the carbonyl moiety to a hydroxyl group (19) leads to a 281-fold affinity drop [43,78]. When docking 18 and 19 into the KOR we observed similar docking poses compared to SalA, but with slight differences (Figure 16).…”

“…In higher concentrations SalA and Salvia divinorum products elicit strong hallucinogenic effects which led to the recreational use of SalA containing products recently [13,14,16,17]. Due to its diterpene structure, SalA lacks the nitrogen atom typical for small molecule OR ligands, like morphin, fentanyl, and buprenorphine, that are mainly alkaloids [16,18]. An ionic interaction between the positive charged nitrogen of the ligand and the carboxylate of D 3.32 (Superscripts denote Ballesteros-Weinstein numbering [19]) was believed to be crucial for OR affinity and activity of small molecule OR ligands thereby serving as an anchor point for the ligand [20][21][22][23].…”

Recreational Drug Misuse and Its Potential Contribution to Male Fertility Levels’ Decline: A Narrative Review

“…A number of human studies, but not all [ 31 ], have reported increased levels of prolactin in opioid abusers. Opioids may also exert a direct effect on testosterone levels through their interaction with the opioid receptors in the testes, where they can influence the expression of genes involved in the antioxidant defense system [ 32 ].…”

The Role of Dynorphin and the Kappa Opioid Receptor in Schizophrenia and Major Depressive Disorder: A Translational Approach

“…Naloxone, naltrexone, and nalmefene have historically been thought to be pan-opioid antagonists at the KOR, MOR, and delta opioid receptor (DOR), while buprenorphine has been shown to be a KOR antagonist and MOR partial agonist (Toll et al 1998). However, some studies have shown evidence for partial KOR agonist effects of nalmefene and naltrexone (Butelman et al 2020). Of note, neither naltrexone nor nalmefene has been shown to produce psychotomimetic effects, indicating that any partial agonism of the KOR is too weak to trigger this mechanism.…”