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Low Doses of Allyphenyline and Cyclomethyline, Effective against Morphine Dependence, Elicit an Antidepressant-like Effect.

ABSTRACT: This study demonstrated that cyclomethyline (2) and the corresponding enantiomers (R)-(-)-2 and (S)-(+)-2, displaying ?2C-adrenoreceptor (AR) agonism/?2A-AR antagonism, similarly to allyphenyline (1) and its enantiomers, significantly decreased the naloxone-precipitated withdrawal symptoms in mice at very low doses. It also highlighted that such positive effects on morphine dependence can even be improved by additional serotoninergic 5-HT1A receptor (5-HT1A-R) activation. Indeed, 1 or the single (S)-(+)-1, 2, or both its enantiomers, all behaving as ?2C-AR agonists/?2A-AR antagonists/5-HT1A-R agonists, alone and at the same low dose, improved morphine withdrawal syndrome and exerted a potent antidepressant-like effect. Therefore, considering the elevated comorbidity between opiate abuse and depressed mood and the benefit of these multifunctional compounds to both disorders, it is possible that they prove more efficacious and less toxic than a cocktail of drugs in managing opioid addiction.

SUBMITTER: Del Bello F

PROVIDER: S-EPMC4025786 | biostudies-other | 2012 Jul

REPOSITORIES: biostudies-other

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Low Doses of Allyphenyline and Cyclomethyline, Effective against Morphine Dependence, Elicit an Antidepressant-like Effect.

Del Bello Fabio F Diamanti Eleonora E Giannella Mario M Mammoli Valerio V Marchioro Carla C Mattioli Laura L Titomanlio Federica F Piergentili Alessandro A Quaglia Wilma W Benedetti Giovanni G Varrone Maurizio M Pigini Maria M

ACS medicinal chemistry letters 20120608 7

This study demonstrated that cyclomethyline (2) and the corresponding enantiomers (R)-(-)-2 and (S)-(+)-2, displaying α2C-adrenoreceptor (AR) agonism/α2A-AR antagonism, similarly to allyphenyline (1) and its enantiomers, significantly decreased the naloxone-precipitated withdrawal symptoms in mice at very low doses. It also highlighted that such positive effects on morphine dependence can even be improved by additional serotoninergic 5-HT1A receptor (5-HT1A-R) activation. Indeed, 1 or the single ...[more]

PMID: 24900506

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Project description:BackgroundOpioid dependence is a major public health issue without optimal therapeutics. This study investigates the potential therapeutic effect of dezocine, a nonaddictive opioid, in opioid dependence in rat models.MethodsDezocine was administered intraperitoneally to a morphine-dependent rat model to investigate its effect on withdrawal and conditioned place preference (CPP). Effect of dezocine on morphine withdrawal syndrome and CPP was analyzed using 2-way analysis of variance (ANOVA) followed by Tukey's post hoc test. Buprenorphine and vehicle solution containing 20% (v/v) dimethyl sulfoxide were used for positive and negative control, respectively. The astrocytes activation in nucleus accumbens was assessed by immunofluorescence assay of glial fibrillary acidic protein. Effect of dezocine and buprenorphine on the internalization of κ opioid receptor (KOR) was investigated using Neuro2A expressing KOR fused to red fluorescent protein tdTomato (KOR-tdT). Buprenorphine and dezocine were screened against 44 G-protein-coupled receptors, ion channels, and transporter proteins using radioligand-binding assay to compare the molecular targets.ResultsThe mean withdrawal score was reduced in rats treated with 1.25 mg·kg dezocine compared to vehicle-treated control animals starting from the day 1 (mean difference: 7.8; 95% confidence interval [CI], 6.35-9.25; P < .0001 by 2-way ANOVA). Significance was observed at all treatment days, including day 7 (mean difference: 2.13; 95% CI, 0.68-3.58; P < .001 by 2-way ANOVA). Furthermore, dezocine inhibited the reinstatement of morphine-induced CPP (mean difference: 314; 95% CI, 197.9-430.1; P < .0001 by 2-way ANOVA) compared to the control group. Chronic morphine administration induced astrocytes activation in nucleus accumbens, which was attenuated by dezocine. Dezocine blocked the agonist-induced KOR internalization in vitro, 1 of the mechanisms involved in the downstream signaling and development of opioid dependence. Dezocine had affinity to norepinephrine and serotonin transporters and sigma-1 receptor, whereas buprenorphine showed no activity against these targets.ConclusionsDezocine could potentially be used to alleviate opioid dependence. Due to the unique molecular target profile different from buprenorphine, it might have important value in studying the mechanisms of morphine dependence and developing novel therapeutic approaches.

Dataset Information

Low Doses of Allyphenyline and Cyclomethyline, Effective against Morphine Dependence, Elicit an Antidepressant-like Effect.

Publications

Low Doses of Allyphenyline and Cyclomethyline, Effective against Morphine Dependence, Elicit an Antidepressant-like Effect.

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