Ramachandran Roshni, Lam Carmen, Yaksh Tony L
Anesthesiology Research, Department of Anesthesiology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Anesthesiology Research, Department of Anesthesiology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Neurobiol Dis. 2015 Jul;79:111-22. doi: 10.1016/j.nbd.2015.04.011. Epub 2015 May 6.
Migraine secondary to meningeal input is referred to extracranial regions innervated by somatic afferents that project to homologous regions in the trigeminal nucleus caudalis (TNC). Reported efficacy of extracranial botulinum toxin (BoNT) in treating migraine is surprising since a local extracranial effect of BoNT cannot account for its effect upon meningeal input. We hypothesize that intradermal BoNT acts through central transport in somatic afferents. Anesthetized C57Bl/6 mice (male) received unilateral supraorbital (SO) injections of BoNT-B (1.5 U/40 μl) or saline. 3 days later, mice received ipsilateral (ipsi)-SO capsaicin (20 μl of 0.5mM solution) or meningeal capsaicin (4 μl of 0.35 μM). Pre-treatment with ipsi-SO BoNT-B i) decreased nocicsponsive ipsilateral wiping behavior following ipsi-SO capsaicin; ii) produced cleavage of VAMP in the V1 region of ipsi-TG and in TG neurons showing WGA after SO injection; iii) reduced expression of c-fos in ipsi-TNC following ipsi-SO capsaicin; iv) reduced c-fos activation and NK-1 internalization in ipsi-TNC secondary to ipsi-meningeal capsaicin; and vi) SO WGA did not label dural afferents. We conclude that BoNT-B is taken up by peripheral afferents and transported to central terminals where it inhibits transmitter release resulting in decreased activation of second order neurons. Further, this study supports the hypothesis that SO BoNT exerts a trans-synaptic action on either the second order neuron (which receives convergent input from the meningeal afferent) or the terminal/TG of the converging meningeal afferent.
继发于脑膜传入的偏头痛会牵涉到由躯体传入神经支配的颅外区域，这些躯体传入神经投射到三叉神经尾侧核（TNC）的同源区域。颅外肉毒杆菌毒素（BoNT）治疗偏头痛的疗效令人惊讶，因为BoNT的局部颅外作用无法解释其对脑膜传入的影响。我们推测皮内注射BoNT是通过躯体传入神经的中枢转运发挥作用。对麻醉的C57Bl/6雄性小鼠进行单侧眶上（SO）注射BoNT-B（1.5 U/40 μl）或生理盐水。3天后，小鼠接受同侧（ipsi）-SO辣椒素（20 μl 0.5 mM溶液）或脑膜辣椒素（4 μl 0.35 μM）。用ipsi-SO BoNT-B预处理：i）减少了ipsi-SO辣椒素后同侧伤害性反应擦拭行为；ii）在ipsi-TG的V1区域和SO注射后显示WGA的TG神经元中产生VAMP裂解；iii）减少ipsi-SO辣椒素后ipsi-TNC中c-fos的表达；iv）减少ipsi-脑膜辣椒素继发的ipsi-TNC中c-fos激活和NK-1内化；以及vi）SO WGA未标记硬脑膜传入神经。我们得出结论，BoNT-B被外周传入神经摄取并转运至中枢终末，在那里它抑制递质释放，导致二级神经元激活减少。此外，本研究支持以下假设：SO BoNT对二级神经元（接收来自脑膜传入神经的汇聚输入）或汇聚脑膜传入神经的终末/TG发挥跨突触作用。
