发作性睡病的药物治疗进展

发作性睡病是致残性白天睡眠增多的最常见原因之一，其治疗旨在减少白天睡眠增多和猝倒，改善夜间睡眠紊乱、睡眠瘫痪及与睡眠有关的幻觉。2019年，组胺H3受体拮抗剂替洛利生（Pitolisant）和多巴胺及去甲肾上腺素再摄取抑制剂索利氨酯（Solriamfetol）分别在欧盟和美国上市，前者具有促醒和抗猝倒作用，后者也有促醒作用，且戒断症状和滥用的发生率更低。目前，控释型羟丁酸钠（FT218）、低钠型羟丁酸盐（JZP-258）、选择性去甲肾上腺素再摄取抑制剂（瑞波西汀，又称AXS-12）以及莫达非尼联合氟卡尼制剂（THN102）等药物仍在开发和测试中，均可作为治疗发作性睡病相关白天睡眠增多和猝倒的潜在药物。本文重点介绍这些最近研发的发作性睡病治疗药物。     

Widespread enhancement of pain sensitivity in MRL/MpJ mice following infraorbital nerve transection

OBJECTIVE Neuropathic pain in humans may spread to regions beyond the area innervated by the injured nerve.This study aims to verify the appearance of wide-spread neuropathic pain following infraorbital nerve transection and investigate the mechanisms underlying wide-spread pain.METHODS The infraorbital nerve of male MRL/MPJ mice was transected(ION-T) to induce trigeminal neuralgia under isoflurane anesthesia.The sensitivities to tactile and heat stimuli of different body parts including the vibrissal pads,hindpaws,and tail were tested after surgery.Activation of microglia in the dorsal horn at levels of medulla(MDH) and L4/L5(SDH) were measured by immunohistochemistry.RESULTS Compared to sham-operated mice,injured mice showed significantly mechanical allodynia,heat allodynia and hyperalgesia in the ipsilateral vibrissal pad,and extraterritorially in the contralateral vibrissal pad,bilateral hindpaws and tail.There was a negative correlation between the evoked pain in denervated area and extraterritorial areas.Microglia in the MDH of injured mice were significantly activated 3 d postoperatively.However,the activation of microglia in L4/L5 SDH occurred until 7 d postoperatively.Moreover,intraperitoneal injection of minocycline inhibited the wide-spread pain abnormalities in the vibrissal pads,hindpaws,and tail.CONCLUSION These results indicate the appearance of wide-spread neuropathic pain following infraorbital nerve transection.Microglia activation may be involved in the mechanisms of this phenomenon.     

大鼠电点燃癫痫和低频率电刺激癫痫灶点对自发性神经病理性疼痛的作用

目的:观察癫痫发生过程和低频率电刺激癫痫灶点对自发性神经病理性疼痛的作用。方法:在大鼠杏仁核植入双极电极,恒流电刺激制备电点燃癫痫模型。在癫痫进展的不同阶段(局灶性癫痫发作和全身性癫痫发作)行坐骨神经和隐神经切断术,制备自发性神经病理性疼痛模型,并对大鼠在神经损伤后63 d内的自噬行为进行等级评分。大鼠分为对照组(n=7),局灶性癫痫组(1～3级,n=5),全身性癫痫组(4～5级,n=7),局灶性癫痫加低频电刺激组(n=4),全身性癫痫加低频电刺激组(n=4)。低频电刺激施加在癫痫灶点杏仁核,从神经切断术后开始至术后第21天。结果:局灶性癫痫组的大鼠自噬行为等级在术后第40～63天显著低于对照组,等级进展的曲线下面积由对照组的308.2±51.57下降到45.80±24.64,自噬发生时间比对照组延迟约32 d,没有1例动物在术后第63天表现出高分值自噬行为,而对照组的高分值发生率为71.4%;全身性癫痫组的大鼠自噬行为与对照组相比仅在开始时间上有明显差异,延迟约16 d;不论是局灶性癫痫还是全身性癫痫的大鼠,在其杏仁核施加低频电刺激后,自噬行为的进展和严重程度均与对照组相似。结论:局灶性癫痫大鼠对神经病理性疼痛的敏感性显著降低,低频电刺激杏仁核可以抑制这种变化。