论文部分内容阅读
临床上迫切需要治疗慢性疼痛的有效药物,该研究关注的是遗传性红斑性肢痛症(IEM)相关的慢性疼痛。研究这个遗传学罕见病不仅可以推进根据患者基因背景来选择药物治疗的精准医学研究,而且这个遗传学罕见病被广泛作为研究常见慢性痛的模式疾病。该病其分子机制是源于电压门控钠通道Nav1.7的功能性突变使得背根感受神经节(DRG)神经元过度兴奋,从而过度发放痛觉信号进入中枢神经系统,进而诱发患者的强烈灼烧痛感。这项双盲/安慰剂对照的研究,旨在验明通过基因分析、结构建模和功能鉴定预测的卡马西平(carbamazepine),能否有效缓解携带Na_v1.7S241T突变的IEM患者的疼痛。功能性磁共振成像(functional magnetic resonance imaging,f MRI)用来评估安慰剂或卡马西平治疗对疼痛相关的大脑活动模式的影响。多电极阵列技术(multielectrode array technology,MEA)是用来评估卡马西平对携带Na_v1.7 S241T突变型通道的DRG神经元动作电位发放的影响。这项研究包括携带Na_v1.7 S241T突变的IEM同一家族的两名患者。研究发现,卡马西平能有效缓解携带Na_v1.7 S241T突变的IEM患者的灼烧痛。卡马西平对疼痛的缓解与大脑活动从价值评估(value)/奖励(reward)、痛觉及情感决策区域向第一和第二体感、运动和顶叶区域的转移相平行。卡马西平也显著降低生理相关的温热刺激诱发的表达Na_v1.7 S241T突变型通道的DRG神经元动作电位的发放,进一步表明卡马西平的重要效用位点是在外周DRG神经元。
There is an urgent need in the clinic for effective treatment of chronic pain, which is focused on chronic pain associated with hereditary erythromelalgia (IEM). Studying this rare genetic disease can advance not only precision medical research that chooses drug treatment based on the patient’s genetic background, but also a genetically rare disease that is widely used as a model disease for studying common chronic pain. Its molecular mechanism is derived from the functional mutation of the voltage-gated sodium channel Nav1.7 that causes over-stimulation of the dorsal root ganglion (DRG) neurons, thereby over-releasing pain signals into the central nervous system and thereby inducing intense burning of the patient Burning pain. This double-blind, placebo-controlled study aims to demonstrate that carbamazepine, predicted by genetic analysis, structural modeling and functional characterization, can effectively relieve pain in IEM patients harboring the Na_v1.7S241T mutation. Functional magnetic resonance imaging (f MRI) was used to assess the effect of placebo or carbamazepine treatment on pain-related brain activity patterns. Multielectrode array technology (MEA) was used to assess the effect of carbamazepine on the release of action potential in DRG neurons carrying the Na_v1.7 S241T mutant channel. This study included two patients in the same family of IEMs carrying the Na_v1.7 S241T mutation. The study found that carbamazepine can effectively alleviate the burning pain of IEM patients carrying Na_v1.7 S241T mutation. Carbamazepine relieves pain and parallels brain activity from the value / reward, pain, and emotional decision-making regions to the first and second somatosensory, motor and parietal regions. Carbamazepine also significantly reduced the release of DRG neuronal action potential in Na_v1.7 S241T mutant channel induced by physiologic warm stimulus, which further indicated that the important site of carbamazepine was peripheral DRG neurons.