Pregabalin silences oxaliplatin-activated sensory neurons to relieve cold allodynia

Oxaliplatin is a platinum-based chemotherapeutic agent that causes cold and mechanical allodynia in up to 90% of patients. Silent Nav1.8-positive nociceptive cold sensors have been shown to be unmasked by oxaliplatin and other neuropathic insults. This event has been causally linked to the development of cold and mechanical allodynia. Pregabalin is an anti-epileptic and analgesic drug that acts through a calcium channel α2δ1 subunit to lower neurotransmitter release. Recent data also suggest pregabalin can act on NMDA receptors and other proteins, but the site of analgesic action has been considered to be the central nervous system. We examined the effects of pregabalin on oxaliplatin -evoked unmasking of cold sensitive neurons using mice expressing GCaMP3 driven by a Pirt promoter in all sensory neurons. We found that in mice treated with oxaliplatin, intravenous injection of pregabalin significantly decreased cold allodynia. Interestingly, pregabalin also decreased the number of sensory neurons responding to cold nociceptive stimuli by altering their excitability and their temperature thresholds. These silenced neurons are medium/large cells responding to both painful mechanical and cold stimuli, corresponding to the “silent” cold sensors that become active in numerous neuropathic pain models. Deletion of α2δ1 subunits abolished the effects of pregabalin on both cold allodynia and the silencing of sensory neuron unmasked by oxaliplatin. Taken together, these results define a novel, peripheral inhibitory effect of pregabalin on the excitability of silent cold-sensing neurons in a model of oxaliplatin-dependent cold allodynia.

奥沙利铂（Oxaliplatin）是一种铂类化疗药物，可在高达90%的患者中引发冷性痛觉超敏与机械性痛觉超敏。已有研究证实，奥沙利铂及其他神经病理性损伤可显露沉默的Nav1.8阳性伤害感受性冷感受器（Silent Nav1.8-positive nociceptive cold sensors），该现象与冷性及机械性痛觉超敏的发生存在直接因果关联。普瑞巴林（Pregabalin）是一款兼具抗癫痫与镇痛活性的药物，可通过作用于钙通道α2δ1亚基降低神经递质释放。近期研究还提示，普瑞巴林可作用于N-甲基-D-天冬氨酸（NMDA）受体及其他蛋白，但此前学界普遍认为其镇痛作用的靶点位于中枢神经系统。我们采用在所有感觉神经元中以Pirt启动子（Pirt promoter）驱动表达GCaMP3的小鼠模型，探究了普瑞巴林对奥沙利铂诱导的冷敏感神经元显露的调控作用。实验发现，在经奥沙利铂处理的小鼠中，静脉注射普瑞巴林可显著减轻冷性痛觉超敏。值得注意的是，普瑞巴林还通过改变感觉神经元的兴奋性与温度阈值，减少了对冷伤害性刺激产生响应的神经元数量。此类被沉默的神经元为可同时响应伤害性机械刺激与冷刺激的中/大型细胞，对应于在多种神经病理性疼痛模型中被激活的"沉默"冷感受器。敲除α2δ1亚基可完全消除普瑞巴林对冷性痛觉超敏以及奥沙利铂所显露的感觉神经元沉默效应的调控作用。综上，本研究结果揭示了普瑞巴林在奥沙利铂诱导的冷性痛觉超敏模型中，对沉默冷感知神经元兴奋性的一种全新外周抑制作用。