Gravielle María Clara
Instituto de Investigaciones Farmacológicas, Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad de Buenos Aires, Junín 956, C1113AAD Buenos Aires, Argentina.
Pharmacol Res. 2016 Jul;109:92-100. doi: 10.1016/j.phrs.2015.12.030. Epub 2015 Dec 28.
Benzodiazepines have been used clinically for more than 50 years to treat disorders such as insomnia, anxiety, and epilepsy, as well as to aid muscle relaxation and anesthesia. The therapeutic index for benzodiazepines if very high and the toxicity is low. However, their usefulness is limited by the development of either or both tolerance to most of their pharmacological actions and dependence. Tolerance develops at different rates depending on the pharmacological action, suggesting the existence of distinct mechanisms for each behavioral parameter. Alternatively, multiple mechanisms could coexist depending on the subtype of GABAA receptor expressed and the brain region involved. Because most of the pharmacological actions of benzodiazepines are mediated through GABAA receptor binding, adaptive alterations in the number, structure, and/or functions of these receptors may play an important role in the development of tolerance. This review is focused on the regulation of GABAA receptors induced by long-term benzodiazepine exposure and its relationship with the development of tolerance. Understanding the mechanisms behind benzodiazepine tolerance is critical for designing drugs that could maintain their efficacy during long-term treatments.
苯二氮䓬类药物已在临床上使用了50多年，用于治疗失眠、焦虑和癫痫等疾病，以及辅助肌肉松弛和麻醉。苯二氮䓬类药物的治疗指数非常高且毒性低。然而，它们的效用受到对其大多数药理作用产生耐受性和依赖性中的一种或两种的限制。耐受性根据药理作用以不同速率发展，这表明每个行为参数存在不同的机制。或者，根据所表达的GABAA受体亚型和所涉及的脑区，多种机制可能共存。由于苯二氮䓬类药物的大多数药理作用是通过与GABAA受体结合介导的，这些受体在数量、结构和/或功能上的适应性改变可能在耐受性的发展中起重要作用。本综述聚焦于长期苯二氮䓬暴露诱导的GABAA受体调节及其与耐受性发展的关系。了解苯二氮䓬耐受性背后的机制对于设计在长期治疗期间能够维持其疗效的药物至关重要。
