Burstein Rami, Jakubowski Moshe
Departments of Anesthesia and Critical Care, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Ann Neurol. 2004 Jan;55(1):27-36. doi: 10.1002/ana.10785.
We have shown that the development of cutaneous allodynia (exaggerated skin sensitivity) during migraine is detrimental to the anti-migraine action of the 5HT(IB/ID) receptor agonists known is triptans. Because cutaneous allodynia is a manifestation of sensitization of central trigeminovascular neurons, we examined whether triptan treatment can intercept such sensitization before its initiation or after its establishment in our rat model for cutaneous allodynia induced by intracranial pain. Single-unit recordings were obtained from spinal trigeminal neurons that proved to received convergent inputs from the dura and facial skin. The effects of sumatriptan (300 microg/kg i.v.) on central sensitization induced by topical application of inflammatory soup (IS) on the dura were determined when the drug was administered either 2 h after IS (late intervention) or at the same time as IS (early intervention). Late sumatriptan intervention counteracted two aspects of central sensitization: dural receptive fields, which initially expanded by IS, shrunk back after treatment; neuronal response threshold to dural indentation, which initially decreased after IS, increased after sumatriptan. On the other hand, late sumatriptan intervention did not reverse other aspects of central sensitization: spontaneous firing rate and neuronal response magnitude to skin brushing which initially increased after IS, remained elevated after sumatriptan; response threshold to heating of the skin, which initially dropped after IS, remained low after sumatriptan. Early sumatriptan intervention effectively blocked the development of all aspects of central sensitization expected to be induced 2 h after IS application: dural receptive fields did not expand; neuronal response threshold to dural indentation and skin stimulation did not decrease; spontaneous firing rate did not increase. The early treatment results suggest that triptan action provides a powerful means of preventing the initiation of central sensitization triggered by chemical stimulation of meningeal nociceptors. The late treatment results suggest that triptan action is insufficient to counteract an already established central sensitization. Thus, triptan action appears to be exerted directly on peripheral rather than central trigeminovascular neurons.
我们已经表明，偏头痛期间皮肤异常性疼痛（皮肤敏感性增强）的发展不利于已知为曲坦类药物的5HT(IB/ID)受体激动剂的抗偏头痛作用。由于皮肤异常性疼痛是中枢三叉神经血管神经元致敏的一种表现，我们在由颅内疼痛诱导的皮肤异常性疼痛大鼠模型中，研究了曲坦类药物治疗能否在致敏开始前或致敏形成后阻断这种致敏。从脊髓三叉神经神经元获得单单位记录，这些神经元被证明接受来自硬脑膜和面部皮肤的汇聚输入。当药物在炎症汤（IS）局部应用于硬脑膜2小时后（晚期干预）或与IS同时给药（早期干预）时，测定舒马曲坦（300微克/千克静脉注射）对硬脑膜局部应用IS诱导的中枢致敏的影响。舒马曲坦晚期干预抵消了中枢致敏的两个方面：硬脑膜感受野最初因IS而扩大，治疗后缩小；对硬脑膜压痕的神经元反应阈值最初在IS后降低，在舒马曲坦后升高。另一方面，舒马曲坦晚期干预并未逆转中枢致敏的其他方面：自发放电率和对皮肤轻刷的神经元反应幅度最初在IS后增加，在舒马曲坦后仍保持升高；对皮肤加热的反应阈值最初在IS后下降，在舒马曲坦后仍保持较低。舒马曲坦早期干预有效地阻断了预期在IS应用2小时后诱导的中枢致敏各方面的发展：硬脑膜感受野未扩大；对硬脑膜压痕和皮肤刺激的神经元反应阈值未降低；自发放电率未增加。早期治疗结果表明，曲坦类药物的作用提供了一种强大的手段来预防由脑膜伤害感受器的化学刺激引发的中枢致敏的起始。晚期治疗结果表明，曲坦类药物的作用不足以抵消已经形成的中枢致敏。因此，曲坦类药物的作用似乎直接作用于外周而非中枢三叉神经血管神经元。
