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      Racemic Salsolinol and its Enantiomers Act as Agonists of the μ-Opioid Receptor by Activating the Gi Protein-Adenylate Cyclase Pathway

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          Abstract

          Background: Several studies have shown that the ethanol-derived metabolite salsolinol (SAL) can activate the mesolimbic system, suggesting that SAL is the active molecule mediating the rewarding effects of ethanol. In vitro and in vivo studies suggest that SAL exerts its action on neuron excitability through a mechanism involving opioid neurotransmission. However, there is no direct pharmacologic evidence showing that SAL activates opioid receptors.

          Methods: The ability of racemic (R/S)-SAL, and its stereoisomers (R)-SAL and (S)-SAL, to activate the μ-opioid receptor was tested in cell-based (light-emitting) receptor assays. To further characterizing the interaction of SAL stereoisomers with the μ-opioid receptor, a molecular docking study was performed using the crystal structure of the μ-opioid receptor.

          Results: This study shows that SAL activates the μ-opioid receptor by the classical G protein-adenylate cyclase pathway with an half-maximal effective concentration (EC 50) of 2 × 10 −5 M. The agonist action of SAL was fully blocked by the μ-opioid antagonist naltrexone. The EC 50 for the purified stereoisomers (R)-SAL and (S)-SAL were 6 × 10 −4 M and 9 × 10 −6 M respectively. It was found that the action of racemic SAL on the μ-opioid receptor did not promote the recruitment of β-arrestin. Molecular docking studies showed that the interaction of (R)- and (S)-SAL with the μ-opioid receptor is similar to that predicted for the agonist morphine.

          Conclusions: It is shown that (R)-SAL and (S)-SAL are agonists of the μ-opioid receptor. (S)-SAL is a more potent agonist than the (R)-SAL stereoisomer. In silico analysis predicts a morphine-like interaction between (R)- and (S)-SAL with the μ-opioid receptor. These results suggest that an opioid action of SAL or its enantiomers is involved in the rewarding effects of ethanol.

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          Most cited references45

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          Crystal structure of the μ-opioid receptor bound to a morphinan antagonist

          Summary Opium is one of the world’s oldest drugs, and its derivatives morphine and codeine are among the most used clinical drugs to relieve severe pain. These prototypical opioids produce analgesia as well as many of their undesirable side effects (sedation, apnea and dependence) by binding to and activating the G-protein-coupled μ-opioid receptor (μOR) in the central nervous system. Here we describe the 2.8 Å crystal structure of the μOR in complex with an irreversible morphinan antagonist. Compared to the buried binding pocket observed in most GPCRs published to date, the morphinan ligand binds deeply within a large solvent-exposed pocket. Of particular interest, the μOR crystallizes as a two-fold symmetric dimer through a four-helix bundle motif formed by transmembrane segments 5 and 6. These high-resolution insights into opioid receptor structure will enable the application of structure-based approaches to develop better drugs for the management of pain and addiction.
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            Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats.

            The effect of various drugs on the extracellular concentration of dopamine in two terminal dopaminergic areas, the nucleus accumbens septi (a limbic area) and the dorsal caudate nucleus (a subcortical motor area), was studied in freely moving rats by using brain dialysis. Drugs abused by humans (e.g., opiates, ethanol, nicotine, amphetamine, and cocaine) increased extracellular dopamine concentrations in both areas, but especially in the accumbens, and elicited hypermotility at low doses. On the other hand, drugs with aversive properties (e.g., agonists of kappa opioid receptors, U-50,488, tifluadom, and bremazocine) reduced dopamine release in the accumbens and in the caudate and elicited hypomotility. Haloperidol, a neuroleptic drug, increased extracellular dopamine concentrations, but this effect was not preferential for the accumbens and was associated with hypomotility and sedation. Drugs not abused by humans [e.g., imipramine (an antidepressant), atropine (an antimuscarinic drug), and diphenhydramine (an antihistamine)] failed to modify synaptic dopamine concentrations. These results provide biochemical evidence for the hypothesis that stimulation of dopamine transmission in the limbic system might be a fundamental property of drugs that are abused.
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              Opioids excite dopamine neurons by hyperpolarization of local interneurons.

              Increased activity of dopamine-containing neurons in the ventral tegmental area is necessary for the reinforcing effects of opioids and other abused drugs. Intracellular recordings from these cells in slices of rat brain in vitro showed that opioids do not affect the principal (dopamine-containing) neurons but hyperpolarize secondary (GABA-containing) interneurons. Experiments with agonists and antagonists selective for opioid receptor subtypes indicated that the hyperpolarization of secondary cells involved the mu-receptor. Most principal cells showed spontaneous bicuculline-sensitive synaptic potentials when the extracellular potassium concentration was increased from 2.5 to 6.5 or 10.5 mM; these were prevented by TTX and assumed to result from action potentials arising in slightly depolarized local interneurons. The frequency of these synaptic potentials, but not their amplitudes, was reduced by opioids selective for mu-receptors. It is concluded that hyperpolarization of the interneurons by opioids reduces the spontaneous GABA-mediated synaptic input to the dopamine cells. In vivo, this would lead to excitation of the dopamine cells by disinhibition, which would be expected to contribute to the positive reinforcement seen with mu-receptor agonists such as morphine and heroin.
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                Author and article information

                Contributors
                Journal
                Front Behav Neurosci
                Front Behav Neurosci
                Front. Behav. Neurosci.
                Frontiers in Behavioral Neuroscience
                Frontiers Media S.A.
                1662-5153
                23 January 2017
                2016
                : 10
                : 253
                Affiliations
                [1] 1Program of Molecular and Clinical Pharmacology, Faculty of Medicine, Institute of Biomedical Sciences, University of Chile Santiago, Chile
                [2] 2Department of Environmental Health Sciences, Yale School of Public Health New Haven, CT, USA
                [3] 3Department of Analytical and Inorganic Chemistry, Faculty of Chemical and Pharmaceutical Sciences, University of Chile Santiago, Chile
                [4] 4Department of Pharmacological and Toxicological Chemistry, Faculty of Chemical and Pharmaceutical Sciences, University of Chile Santiago, Chile
                Author notes

                Edited by: Merce Correa, Jaume I University, Spain

                Reviewed by: Elio Acquas, University of Cagliari, Italy; Lucia Hipolito, University of Valencia, Spain

                *Correspondence: Mario Rivera-Meza mario.rivera@ 123456ciq.uchile.cl
                Article
                10.3389/fnbeh.2016.00253
                5253357
                28167903
                446a6441-d454-4fe0-967f-e76911ffef7e
                Copyright © 2017 Berríos-Cárcamo, Quintanilla, Herrera-Marschitz, Vasiliou, Zapata-Torres and Rivera-Meza.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution and reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 25 October 2016
                : 28 December 2016
                Page count
                Figures: 6, Tables: 1, Equations: 0, References: 57, Pages: 11, Words: 8242
                Funding
                Funded by: Fondo Nacional de Desarrollo Científico y Tecnológico 10.13039/501100002850
                Award ID: 11130241
                Award ID: 1120072
                Funded by: Comisión Nacional de Investigación Científica y Tecnológica 10.13039/501100002848
                Award ID: 2013-21130865
                Funded by: National Institutes of Health 10.13039/100000002
                Award ID: AA022057
                Award ID: AA021724
                Categories
                Neuroscience
                Original Research

                Neurosciences
                salsolinol,μ-opioid receptor,naltrexone,β-arrestin,molecular docking
                Neurosciences
                salsolinol, μ-opioid receptor, naltrexone, β-arrestin, molecular docking

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