The Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada Center for Sensory-Motor Interaction (SMI), Dept. of Health Science and Technology, Aalborg University, Aalborg, Denmark.
Pain. 2010 Dec;151(3):606-616. doi: 10.1016/j.pain.2010.07.029. Epub 2010 Aug 21.
The mechanism by which intramuscular injection of BoNTA into the craniofacial muscles decreases migraine headaches is not known. In a blinded study, the effect of BoNTA on the mechanical and chemical responsiveness of individual temporalis muscle nociceptors and muscle neurogenic vasodilation was investigated in female rats. Mechanical threshold was measured for 3h following intramuscular injection of BoNTA or vehicle, and for 10 min after a subsequent injection of the algogen glutamate. Injection of BoNTA significantly increased the mechanical threshold of muscle nociceptors without altering the muscle surface temperature and blocked glutamate-induced mechanical sensitization and neurogenic vasodilation. None of these effects were reproduced by pancuronium-induced muscle paralysis. Western blot analysis of temporalis muscles indicated that BoNTA significantly decreased SNAP-25. Measurement of interstitial glutamate concentration with a glutamate biosensor indicated that BoNTA significantly reduced glutamate concentrations. The mechanical sensitivity of muscle nociceptors is modulated by glutamate concentration through activation of peripheral NMDA receptors. Immunohistochemical experiments were conducted and they indicated that half of the NMDA-expressing temporalis nerve fibers co-expressed substance P or CGRP. Additional electrophysiology experiments examined the effect of antagonists for NMDA, CGRP and NK1 receptors on glutamate-induced effects. Glutamate-induced mechanical sensitization was only blocked by the NMDA receptor antagonist, but muscle neurogenic vasodilation was attenuated by NMDA or CGRP receptor antagonists. These data suggest that injection of BoNTA into craniofacial muscles acts to decrease migraine headaches by rapidly decreasing the mechanical sensitivity of temporalis muscle nociceptors through inhibition of glutamate release and by attenuating the provoked release of CGRP from muscle nociceptors.
肉毒毒素 A 经肌内注射入颅面肌肉后可减轻偏头痛，其作用机制尚不清楚。在一项盲法研究中，研究人员观察了肉毒毒素 A 对雌性大鼠颞肌伤害感受器的机械和化学反应性以及肌源性神经扩张的影响。在肌内注射肉毒毒素 A 或载体后 3 小时测量机械阈值，并在随后注射致痛剂谷氨酸后 10 分钟测量。肉毒毒素 A 注射可显著提高肌伤害感受器的机械阈值，而不改变肌肉表面温度，并阻断谷氨酸引起的机械致敏和肌源性神经扩张。这些作用均不能被潘库溴铵诱导的肌肉麻痹所复制。颞肌的 Western blot 分析表明，肉毒毒素 A 可显著降低 SNAP-25 的水平。使用谷氨酸生物传感器测量细胞间隙谷氨酸浓度表明，肉毒毒素 A 可显著降低谷氨酸浓度。肌伤害感受器的机械敏感性通过激活外周 NMDA 受体来调节谷氨酸浓度。免疫组织化学实验表明，有一半表达 NMDA 的颞肌神经纤维共表达 P 物质或 CGRP。进一步的电生理实验研究了 NMDA、CGRP 和 NK1 受体拮抗剂对谷氨酸诱导作用的影响。谷氨酸诱导的机械致敏仅被 NMDA 受体拮抗剂阻断，而肌源性神经扩张则被 NMDA 或 CGRP 受体拮抗剂减弱。这些数据表明，肉毒毒素 A 注射入颅面肌肉可通过抑制谷氨酸释放迅速降低颞肌伤害感受器的机械敏感性，并通过减弱 CGRP 从肌伤害感受器的诱发性释放来减轻偏头痛。
