Baclofen-Induced Neuro-Respiratory Toxicity in the Rat: Contribution of Tolerance and Characterization of Withdrawal Syndrome.

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.

• Authors: Magali Chartier, Salma Tannous, Nadia Benturquia, Laurence Labat, Rafael Reis, Patricia Risède, Lucie Chevillard, Bruno Mégarbane
• Journal: Toxicological sciences : an official journal of the Society of Toxicology (Toxicol Sci) Vol. 164 Issue 1 Pg. 153-165 (07 01 2018) ISSN: 1096-0929 [Electronic] United States
• PMID: 29945230 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Baclofen

Topics

• Animals
• Baclofen (administration & dosage, pharmacokinetics, toxicity)
• Brain (metabolism)
• Dose-Response Relationship, Drug
• Drug Tolerance
• Male
• Neurotoxicity Syndromes (etiology)
• Rats, Sprague-Dawley
• Respiratory Insufficiency (chemically induced)
• Substance Withdrawal Syndrome
• Tissue Distribution