Analgesia and unwanted benzodiazepine effects in point-mutated mice expressing only one benzodiazepine-sensitive GABAA receptor subtype.
Analgesia and unwanted benzodiazepine effects in point-mutated mice expressing only one benzodiazepine-sensitive GABAA receptor subtype.
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DOI：
10.1038/ncomms7803
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发表时间：
2015-04-13
影响因子：
16.6
通讯作者：
Zeilhofer HU
中科院分区：
文献类型：
--
作者：
Ralvenius WT;Benke D;Acuña MA;Rudolph U;Zeilhofer HU
GABAA受体（BDZ）的苯二氮卓类结合位点激动剂通过GABAA受体（GABAAR）的四种亚型（α1、α2、α3和α5）增强突触抑制。当应用于脊髓时，它们减轻病理性疼痛;然而，全身给药后的疗效不足和不期望的作用妨碍了它们在常规疼痛治疗中的使用。以前的工作表明，亚型选择性药物可能允许分离所需的抗痛觉过敏从不必要的影响，但缺乏选择性药物迄今阻止了系统的分析。在这里，我们使用了四个品系的三重GABAAR点突变小鼠，这些小鼠一次只表达一种苯二氮卓类敏感的GABAAR亚型，以证明仅靶向α 2GABAAR可实现强抗痛觉过敏和降低副作用（即无镇静、运动障碍和耐受性发展）。在这些小鼠中进行的其他药代动力学和药效学分析解释了为什么非选择性BDZ不能实现临床相关的抗痛觉过敏。这些发现应该促进创新的亚型选择性BDZ的发展，用于新的适应症，如慢性疼痛。 苯二氮卓（BDZ）靶向GABAA受体以减轻疼痛，但这些也会引起副作用。在这里，作者使用小鼠，其中只有一个GABAA受体是BDZ敏感的时间，以确定α2GABAA作为受体，提供最大的镇痛活性，但最小的副作用，响应BDZ。
Agonists at the benzodiazepine-binding site of GABAA receptors (BDZs) enhance synaptic inhibition through four subtypes (α1, α2, α3 and α5) of GABAA receptors (GABAAR). When applied to the spinal cord, they alleviate pathological pain; however, insufficient efficacy after systemic administration and undesired effects preclude their use in routine pain therapy. Previous work suggested that subtype-selective drugs might allow separating desired antihyperalgesia from unwanted effects, but the lack of selective agents has hitherto prevented systematic analyses. Here we use four lines of triple GABAAR point-mutated mice, which express only one benzodiazepine-sensitive GABAAR subtype at a time, to show that targeting only α2GABAARs achieves strong antihyperalgesia and reduced side effects (that is, no sedation, motor impairment and tolerance development). Additional pharmacokinetic and pharmacodynamic analyses in these mice explain why clinically relevant antihyperalgesia cannot be achieved with nonselective BDZs. These findings should foster the development of innovative subtype-selective BDZs for novel indications such as chronic pain. Benzodiazepines (BDZs) target GABAA receptors to alleviate pain but these also cause side effects. Here the authors use mice in which only one GABAA receptor is BDZ-sensitive at a time to identify α2GABAA as the receptor that provides maximal analgesic activity but minimal side-effects in response to BDZs.