Carisoprodol Intoxications and Serotonergic Features

Bramness, Jørgen G.; Mørland, Jörg; Sørlid, Hanne Kristin; Rudberg, N; Jacobsen, Dag

doi:10.1081/clt-45020

Cited by 23 publications

(7 citation statements)

References 31 publications

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“…In addition, non-GABAergic compounds have not been tested in the carisoprodol-trained rats, so it is possible other receptors may also contribute to the mechanism of action of carisoprodol. For example, meprobamate has been shown to inhibit NMDA-activated currents (Rho et al, 1997), and carisoprodol toxicity has been described as having characteristics similar to those of serotonin syndrome (Bramness et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Carisoprodol-Mediated Modulation of GABA_A Receptors: In Vitro and in Vivo Studies

González¹,

Gatch²,

Taylor³

et al. 2009

J Pharmacol Exp Ther

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Carisoprodol is a frequently prescribed muscle relaxant. In recent years, this drug has been increasingly abused. The effects of carisoprodol have been attributed to its metabolite, meprobamate, a controlled substance that produces sedation via GABA A receptors (GABA A Rs). Given the structural similarities between carisoprodol and meprobamate, we used electrophysiological and behavioral approaches to investigate whether carisoprodol directly affects GABA A R function. In whole-cell patch-clamp studies, carisoprodol allosterically modulated and directly activated human ␣1␤2␥2 GABA A R function in a barbiturate-like manner. At millimolar concentrations, inhibitory effects were apparent. Similar allosteric effects were not observed for homomeric 1 GABA or glycine ␣1 receptors. In the absence of GABA, carisoprodol produced picrotoxin-sensitive, inward currents that were significantly larger than those produced by meprobamate, suggesting carisoprodol may directly produce GABAergic effects in vivo. When administered to mice via intraperitoneal or oral routes, carisoprodol elicited locomotor depression within 8 to 12 min after injection. Intraperitoneal administration of meprobamate depressed locomotor activity in the same time frame. In drug discrimination studies with carisoprodol-trained rats, the GABAergic ligands pentobarbital, chlordiazepoxide, and meprobamate each substituted for carisoprodol in a dose-dependent manner. In accordance with findings in vitro, the discriminative stimulus effects of carisoprodol were antagonized by a barbiturate antagonist, bemegride, but not by the benzodiazepine site antagonist, flumazenil. The results of our studies in vivo and in vitro collectively suggest the barbiturate-like effects of carisoprodol may not be due solely to its metabolite, meprobamate. Furthermore, the functional traits we have identified probably contribute to the abuse potential of carisoprodol.

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Section: Discussionmentioning

confidence: 99%

Carisoprodol-Mediated Modulation of GABA_A Receptors: In Vitro and in Vivo Studies

González¹,

Gatch²,

Taylor³

et al. 2009

J Pharmacol Exp Ther

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“…Meprobamate has a half-life that is nearly 8-fold longer than carisoprodol (Bramness et al, 2005; Olsen et al, 1994), the latter being undetectable in plasma of mice 2 hr following a 600 mg/kg dose (National Toxicology Program, 2000). Thus, accumulation of carisoprodol under any condition in the current study is unlikely, whereas a continuous exposure to meprobamate would be expected throughout the studies.…”

Section: Discussionmentioning

confidence: 99%

Carisoprodol tolerance and precipitated withdrawal

Gatch¹,

Nguyen²,

Carbonaro³

et al. 2012

Drug and Alcohol Dependence

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Aims Carisoprodol is a muscle relaxant that acts at the GABAA receptor. Concerns about the abuse liability of carisoprodol are increasing, but evidence that carisoprodol produces tolerance and a significant withdrawal syndrome has yet to be established. The purpose of the current study was to determine if repeated administration of carisoprodol produces tolerance and withdrawal signs in a mouse model. Methods Carisoprodol (0, 100, 200, 300, or 500 mg/kg bid, i.p.) was administered to Swiss-Webster mice for 4 days and loss-of-righting reflex was measured 20 to 30 minutes following each administration. On the fourth day, bemegride (20 mg/kg), flumazenil (20 mg/kg), or vehicle was administered following carisoprodol and withdrawal signs were measured. Separate groups of mice receiving the same treatment regimen and dose range were tested for spontaneous withdrawal at 6, 12 and 24 hr after the last dose of carisoprodol. Results The righting reflex was dose-dependently impaired following the first administration of carisoprodol. A 75 to 100% decrease in the magnitude of the impairment occurred over the four days of exposure, indicating the development of tolerance to the carisoprodol-elicited loss-of-righting reflex. Withdrawal signs were not observed within 24 hours following spontaneous withdrawal; however, bemegride and flumazenil each precipitated withdrawal within 15 to 30 min of administration. Conclusions Carisoprodol treatment resulted in tolerance and antagonist-precipitated withdrawal, suggesting it may have an addiction potential similar to that of other long-acting benzodiazepine or barbiturate compounds.

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“…Carisoprodol may result in a variety of adverse effects that impact various organ systems; such as: the central nervous system (drowsiness, lightheadedness, dizziness, fatigue, loss of motor coordination, insomnia, stupor, coma), cardiovascular function (tachycardia, facial flushing), respiratory function (dyspnea, respiratory depression), musculoskeletal function (hypertonia, tremor), skin responses (rash, hives), gastrointestinal responses (nausea, vomiting), and ocular function (blurred or burning vision, nystagmus) [1,13]. Carisprodol overdose has also been reported to result in an unusual movement disorder involving agitation, hypertonia, and myoclonic encephalopathy [14,15]. The effects of carisoprodol may be potentiated with the use of other substances such as alcohol or other central nervous system depressants [1].…”

Section: Introductionmentioning

confidence: 99%

Carisoprodol abuse in Texas, 1998–2003

Forrester

2006

J. Med. Toxicol.

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Introduction: Texas poison centers identified carisoprodol as a skeletal muscle relaxant that is subject to abuse, and this investigation explores the abuse reported by Texas poison centers.Methods: This study used data from six Texas poison centers to describe the epidemiology of carisoprodol abuse and drug identification (ID) calls from 1998 to 2003.Results: Drug ID and abuse calls were 217% higher in 2003 than in 1998. Although eastern and central Texas contains 43% of the state's population, this region reported 77% of all drug ID calls and 64% of abuse calls. Male patients accounted for 51% of abuse calls and 37% of other human exposure calls. Patients from 13 to 19 years of age accounted for 17% of abuse calls and 9% of other human exposure calls. Among those human exposure calls with a known medical outcome, a higher percentage of abuse calls involved minor effects while a greater proportion of other human exposure calls involved outcomes that ranged from moderate effects to death.Conclusions: Carisoprodol abuse is increasing in Texas and is substantially more common in the eastern part of the state. Carisoprodol abuse is much more likely, than other types of adverse carisoprodol exposures, to involve males and adolescents; and it less likely to involve adverse medical outcomes.

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Carisoprodol Intoxications and Serotonergic Features

Cited by 23 publications

References 31 publications

Carisoprodol-Mediated Modulation of GABA_A Receptors: In Vitro and in Vivo Studies

Carisoprodol-Mediated Modulation of GABA_A Receptors: In Vitro and in Vivo Studies

Carisoprodol tolerance and precipitated withdrawal

Carisoprodol abuse in Texas, 1998–2003

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Carisoprodol Intoxications and Serotonergic Features

Cited by 23 publications

References 31 publications

Carisoprodol-Mediated Modulation of GABAA Receptors: In Vitro and in Vivo Studies

Carisoprodol-Mediated Modulation of GABAA Receptors: In Vitro and in Vivo Studies

Carisoprodol tolerance and precipitated withdrawal

Carisoprodol abuse in Texas, 1998–2003

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Carisoprodol-Mediated Modulation of GABA_A Receptors: In Vitro and in Vivo Studies

Carisoprodol-Mediated Modulation of GABA_A Receptors: In Vitro and in Vivo Studies