Riluzole decreases the abstinence syndrome and physical dependence in morphine-dependent mice

Sepúlveda, Jacqueline; Astorga, Juan G; Contreras, Enrique

doi:10.1016/s0014-2999(99)00503-8

Cited by 17 publications

(9 citation statements)

References 11 publications

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“…Mice were videotaped for 20 min, and the tapes were analyzed by a trained observer who was blinded to all experimental treatments. Various measures were recorded for each mouse including vertical jumping, weight of urine & feces, and body weight loss (Sepulveda et al, 1999; Yano and Takemori, 1977). Each nominal sign was either present or absent, and the number of vertical jumps, and fecal boli for each animal was recorded.…”

Section: Methodsmentioning

confidence: 99%

Behavioral and cellular pharmacology characterization of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan (NAQ) as a mu opioid receptor selective ligand

Zhang¹,

Braithwaite²,

Yuan³

et al. 2014

European Journal of Pharmacology

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Mu opioid receptor (MOR) selective antagonists and partial agonists have been used for the treatment of opioid abuse and addiction. Our recent efforts on the identification of MOR antagonists have provided several novel leads displaying interesting pharmacological profiles. Among them, 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-[(3'-isoquinolyl)acetamido]morphinan (NAQ) showed sub-nanomolar binding affinity to the MOR with significant selectivity over the delta opioid receptor (DOR) and the kappa opioid receptor (KOR). Its central nervous system penetration capacity together with marginal agonism in the MOR–GTPγS binding assay made it a very interesting molecule for developing novel opioid abuse and addiction therapeutic agents. Therefore, further pharmacological characterization was conducted to fully understand its biological profile. At the molecular and cellular level, NAQ not only induced no translocation of β-arrestin2 to the MOR, but also efficaciously antagonized the effect of DAMGO in MOR-βarr2eGFP-U2OS cells in the β-arrestin2 recruitment assay. At the in vivo level, NAQ displayed a potent inhibition of the analgesic effect of morphine in the tail-flick assay (ID50 = 1.19 mg/kg). NAQ (10 mg/kg) also significantly decreased the hyper-locomotion induced by acute morphine without inducing any vertical jumps. Meanwhile NAQ precipitated lesser withdrawal symptoms in morphine dependent mice than naloxone. In conclusion, NAQ may represent a new chemical entity for opioid abuse and addiction treatment.

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Section: Methodsmentioning

confidence: 99%

Behavioral and cellular pharmacology characterization of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan (NAQ) as a mu opioid receptor selective ligand

Zhang¹,

Braithwaite²,

Yuan³

et al. 2014

European Journal of Pharmacology

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“…Mice were videotaped for 20 min, and the tapes were analyzed by a trained observer who was blinded to all experimental treatments. Various measures were recorded for each mouse including vertical jumping, "wet-dog" shakes, paw tremors, number of fecal boli, presence of diarrhea, and piloerection (Yano and Takemori, 1977;Sepú lveda et al, 1999). Each nominal sign was either present or absent, and the number of paw tremors, body shakes, vertical jumps, and fecal boli for each animal was recorded.…”

mentioning

confidence: 99%

In Vivo Characterization of 6β-Naltrexol, an Opioid Ligand with Less Inverse Agonist Activity Compared with Naltrexone and Naloxone in Opioid-Dependent Mice

Raehal

Lowery²,

Bhamidipati³

et al. 2005

J Pharmacol Exp Ther

138

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The -opioid receptor displays basal signaling activity, which seems to be enhanced by exposure to opioid agonists. This study assesses the in vivo pharmacology of the putative "neutral" antagonist 6␤-naltrexol in comparison to other ligands with varying efficacy, such as naloxone, an inverse agonist in the opioid-dependent state. ICR mice were used to generate full antagonist dose-response curves for naloxone, naltrexone, nalbuphine, and 6␤-naltrexol in blocking acute antinociceptive effects of morphine and precipitating opioid withdrawal in models of physical dependence. 6␤-Naltrexol was roughly equipotent to naloxone and between 4.5-and 10-fold less potent than naltrexone in blocking morphine-induced antinociception and locomotor activity, showing that 6␤-naltrexol enters the central nervous system. In contrast to naloxone and naltrexone, 6␤-naltrexol precipitated only minimal withdrawal at high doses in an acute dependence model and was ϳ77-and 30-fold less potent than naltrexone and naloxone, respectively, in precipitating withdrawal in a chronic dependence model. 6␤-Naltrexol reduced the inverse agonist effects of naloxone in vitro and in vivo, as expected for a neutral antagonist. Therefore, the pharmacological effects of 6␤-naltrexol differ markedly from those of naloxone and naltrexone in the opioid-dependent state. A reduction of withdrawal effects associated with neutral -opioid receptor antagonists may offer advantages in treating opioid overdose and addiction.Basal signaling/constitutive activity of G-protein coupled receptors is now firmly established largely on the basis of in vitro results (Kenakin, 2003(Kenakin, , 2004a, with receptor ligands displaying a range of efficacies from full agonists to full inverse agonists. However, for receptor systems that display constitutive activity, many questions remain to be resolved. 1) Do the in vitro observations translate into changes that can be measured in vivo? 2) Are there clinical applications for inverse agonists versus neutral antagonists? 3) How is basal receptor activity regulated, and how does disease and/or chronic drug exposure alter levels of basal signaling and ligand efficacy? Studies on ␤-adrenergic receptors, for example, suggest that these issues may contribute to patient outcomes in diseases such as congestive heart failure and asthma (Maack et al., 2000;Callaerts-Vegh et al., 2004).We and others have established that the -and ␦-opioid receptors display basal signaling, which is altered by exposure to opioid agonists (Costa and

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“…Regarding the first issue, the dose of riluzole in chronic experiments performed on rodents does indeed range from 1 mg/kg to 40 mg/kg (Besheer, Lepoutre & Hodge, 2009; Carbone, Duty & Rattray, 2012; Fumagalli et al, 2006; Sepulveda, Astorga & Contreras, 1999), and is predominantly 20 mg/kg when used to evoke a neurogenesis response. Therefore, the dose used in our experiment was in the lower range of the therapeutic window.…”

Section: Discussionmentioning

confidence: 99%

Lack of riluzole efficacy in the progression of the neurodegenerative phenotype in a new conditional mouse model of striatal degeneration

Kreiner

Rafa-Zabłocka

Chmielarz

et al. 2017

PeerJ

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BackgroundHuntington’s disease (HD) is a rare familial autosomal dominant neurodegenerative disorder characterized by progressive degeneration of medium spiny neurons (MSNs) located in the striatum. Currently available treatments of HD are only limited to alleviating symptoms; therefore, high expectations for an effective therapy are associated with potential replacement of lost neurons through stimulation of postnatal neurogenesis. One of the drugs of potential interest for the treatment of HD is riluzole, which may act as a positive modulator of adult neurogenesis, promoting replacement of damaged MSNs. The aim of this study was to evaluate the effects of chronic riluzole treatment on a novel HD-like transgenic mouse model, based on the genetic ablation of the transcription factor TIF-IA. This model is characterized by selective and progressive degeneration of MSNs.MethodsSelective ablation of TIF-IA in MSNs (TIF-IAD1RCre mice) was achieved by Cre-based recombination driven by the dopamine 1 receptor (D1R) promoter in the C57Bl/6N mouse strain. Riluzole was administered for 14 consecutive days (5 mg/kg, i.p.; 1× daily) starting at six weeks of age. Behavioral analysis included a motor coordination test performed on 13-week-old animals on an accelerated rotarod (4–40 r.p.m.; 5 min). To visualize the potential effects of riluzole treatment, the striata of the animals were stained by immunohistochemistry (IHC) and/or immunofluorescence (IF) with Ki67 (marker of proliferating cells), neuronal markers (NeuN, MAP2, DCX), and markers associated with neurodegeneration (GFAP, 8OHdG, FluoroJade C). Additionally, the morphology of dendritic spines of neurons was assessed by a commercially available FD Rapid Golgi Stain™ Kit.ResultsA comparative analysis of IHC staining patterns with chosen markers for the neurodegeneration process in MSNs did not show an effect of riluzole on delaying the progression of MSN cell death despite an observed enhancement of cell proliferation as visualized by the Ki67 marker. A lack of a riluzole effect was also reflected by the behavioral phenotype associated with MSN degeneration. Moreover, the analysis of dendritic spine morphology did not show differences between mutant and control animals.DiscussionDespite the observed increase in newborn cells in the subventricular zone (SVZ) after riluzole administration, our study did not show any differences between riluzole-treated and non-treated mutants, revealing a similar extent of the neurodegenerative phenotype evaluated in 13-week-old TIF-IAD1RCre animals. This could be due to either the treatment paradigm (relatively low dose of riluzole used for this study) or the possibility that the effects were simply too weak to have any functional meaning. Nevertheless, this study is in line with others that question the effectiveness of riluzole in animal models and raise concerns about the utility of this drug due to its rather modest clinical efficacy.

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Riluzole decreases the abstinence syndrome and physical dependence in morphine-dependent mice

Cited by 17 publications

References 11 publications

Behavioral and cellular pharmacology characterization of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan (NAQ) as a mu opioid receptor selective ligand

Behavioral and cellular pharmacology characterization of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan (NAQ) as a mu opioid receptor selective ligand

In Vivo Characterization of 6β-Naltrexol, an Opioid Ligand with Less Inverse Agonist Activity Compared with Naltrexone and Naloxone in Opioid-Dependent Mice

Lack of riluzole efficacy in the progression of the neurodegenerative phenotype in a new conditional mouse model of striatal degeneration

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