Department of Neurosurgery, Rhode Island Hospital, Providence, RI, USA.
Department of Neuroscience, Brown University, Providence, RI, USA.
Sci Rep. 2018 Nov 6;8(1):16402. doi: 10.1038/s41598-018-34594-2.
We present a multimodal method combining quantitative electroencephalography (EEG), behavior and pharmacology for pre-clinical screening of analgesic efficacy in vivo. The method consists of an objective and non-invasive approach for realtime assessment of spontaneous nociceptive states based on EEG recordings of theta power over primary somatosensory cortex in awake rats. Three drugs were chosen: (1) pregabalin, a CNS-acting calcium channel inhibitor; (2) EMA 401, a PNS-acting angiotensin II type 2 receptor inhibitor; and (3) minocycline, a CNS-acting glial inhibitor. Optimal doses were determined based on pharmacokinetic studies and/or published data. The effects of these drugs at single or multiple doses were tested on the attenuation of theta power and paw withdrawal latency (PWL) in a rat model of neuropathic pain. We report mostly parallel trends in the reversal of theta power and PWL in response to administration of pregabalin and EMA 401, but not minocycline. We also note divergent trends at non-optimal doses and following prolonged drug administration, suggesting that EEG theta power can be used to detect false positive and false negative outcomes of the withdrawal reflex behavior, and yielding novel insights into the analgesic effects of these drugs on spontaneous nociceptive states in rats.
我们提出了一种结合定量脑电图（EEG）、行为和药理学的多模态方法，用于临床前筛选体内镇痛疗效。该方法包括一种基于清醒大鼠初级体感皮层 theta 功率的 EEG 记录的实时评估自发痛觉状态的客观、非侵入性方法。选择了三种药物：（1）普瑞巴林，一种作用于中枢神经系统的钙通道抑制剂；（2）EMA401，一种作用于周围神经系统的血管紧张素 II 型 2 型受体抑制剂；（3）米诺环素，一种作用于中枢神经系统的神经胶质抑制剂。根据药代动力学研究和/或已发表的数据确定了最佳剂量。在神经病理性疼痛大鼠模型中，测试了这些药物单次或多次给药对 theta 功率和足底退缩潜伏期（PWL）的抑制作用。我们报告了普瑞巴林和 EMA401 给药后 theta 功率和 PWL 逆转的趋势大多相似，但米诺环素则不然。我们还注意到在非最佳剂量和长期药物给药后出现了不同的趋势，表明 EEG theta 功率可用于检测撤回反射行为的假阳性和假阴性结果，并为这些药物对大鼠自发痛觉状态的镇痛效果提供了新的见解。
