Baclofen-Induced Neuro-Respiratory Toxicity in the Rat: Contribution of Tolerance and Characterization of Withdrawal Syndrome. (21st March 2018)

• Record Type: Journal Article
• Authors: Chartier, Magali; Tannous, Salma; Benturquia, Nadia; Labat, Laurence; Reis, Rafael; Risède, Patricia; Chevillard, Lucie; Mégarbane, Bruno
• Is Part Of: Toxicological sciences. Volume 164:Number 1(2018)
• Page Start: 153
• Page End: 165
• Publication Date: 2018-03-21
• Subjects: baclofen -- tolerance -- respiratory depression -- pharmacokinetics -- poisoning -- withdrawal; Toxicology -- Periodicals; Toxicology -- Periodicals; Toxicology; Periodicals; 615.9
• DOI: 10.1093/toxsci/kfy073
• Languages: English
• ISSNs: 1096-6080

Abstract

Abstract: Baclofen, a γ-amino-butyric acid type-B receptor agonist with exponentially increased use at high-dose to facilitate abstinence in chronic alcoholics, is responsible for increasing poisonings. Tolerance and withdrawal syndromes have been reported during prolonged treatment but their contribution to the variability of baclofen-induced neurotoxicity in overdose is unknown. We studied baclofen-induced effects on rat sedation, temperature, and ventilation and modeled baclofen pharmacokinetics and effect/concentration relationships aiming to investigate the consequences of repeated baclofen pretreatment and to characterize withdrawal syndrome. Baclofen-induced dose-dependent sedation ( p <0.01), hypothermia ( p <.001) and respiratory depression ( p <.01) were altered in repeatedly baclofen-pretreated rats ( p <.05). Repeatedly baclofen-pretreated rats did not exhibit respiratory depression following baclofen overdose due to limitations on baclofen-induced increase in inspiratory ( p <.01) and expiratory times ( p <.01). Only slight hypoxemia without respiratory acidosis was observed. Baclofen discontinuation resulted in hyperlocomotion and non-anxiogenic withdrawal symptoms. Regarding pharmacokinetics, repeated baclofen pretreatment increased the peak concentration ( p <.05) and absorption constant rate ( p <.05) and reduced the distribution volume ( p <.0001) and elimination half-life ( p <.05). Analysis of the effect/concentration relationships indicated that plasma baclofen concentration decreases more rapidly than all studied neuro-respiratory effects, in tolerant and non-tolerant rats. Taken together, our findings supported the role of brain distribution in baclofen-induced neurotoxicity expression and its probable involvement in tolerance-related attenuation in addition to physiological adaptations of ventilation. In conclusion, repeated pretreatment attenuates baclofen-attributed neurotoxicity in overdose and results in post-discontinuation withdrawal syndrome. Our findings suggest both pharmacodynamic and pharmacokinetic mechanisms whose relative contributions to the variability of baclofen-induced neurotoxicity in overdose remain to be established.