“精准疼痛医学”成功案例——以基因分析和功能鉴定为指导针对遗传性红斑肢痛症家族患者的药物治疗

发布时间：2018-09-08 16:53

【摘要】：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。
[Abstract]:There is an urgent need for effective drugs for the treatment of chronic pain. This study focuses on chronic pain associated with hereditary erythematous limb pain (IEM). The study of this genetic rare disease not only advances the precise medical study of drug therapy based on the patient's genetic background, but also is widely used as a model disease for the study of common chronic pain. The molecular mechanism of the disease is that the functional mutation of the voltage-gated sodium channel (Nav1.7) makes the (DRG) neurons of the dorsal root sensory ganglion excitedly excited.Thus, the signal of pain is over-transmitted into the central nervous system, which induces the intense burning pain in the patients. The double-blind / placebo-controlled study was designed to determine whether carbamazepine (carbamazepine), predicted by genetic analysis, structural modeling and functional identification, can effectively relieve pain in IEM patients with Na_v1.7S241T mutations. Functional magnetic resonance imaging (functional magnetic resonance imaging,f MRI) was used to assess the effects of placebo or carbamazepine on pain-related brain activity patterns. Multielectrode array technique (multielectrode array technology,MEA) is used to evaluate the effect of carbamazepine on the release of action potential of DRG neurons carrying Na_v1.7 S241T mutant channel. The study included two patients in the same IEM family with the Na_v1.7 S 241T mutation. Carbamazepine was found to be effective in relieving burning pain in IEM patients with Na_v1.7 S 241 T mutation. The pain relief of carbamazepine was parallel to the brain activity shift from (value) / (reward), to the first and second somatosensory, motor and parietal lobe regions. Carbamazepine also significantly reduced the release of action potential of DRG neurons expressing Na_v1.7 S241T mutant channel induced by physiological related thermal stimulation, which further indicated that the important effect site of carbamazepine was in peripheral DRG neurons.
【分类号】：R597

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