Akerman S, Williamson D J, Goadsby P J
Headache Group, Institute of Neurology, Queen Square, London, UK.
Br J Pharmacol. 2003 Oct;140(3):558-66. doi: 10.1038/sj.bjp.0705456. Epub 2003 Aug 26.
Amissense mutation of the CACNA1A gene that encodes the alpha1A subunit of the voltage-dependent P/Q-type calcium channel has been discovered in patients suffering from familial hemiplegic migraine. This suggested that calcium channelopathies may be involved in migraine more broadly, and established the importance of genetic mechanisms in migraine. Channelopathies share many clinical characteristics with migraine, and thus exploring calcium channel functions in the trigeminovascular system may give insights into migraine pathophysiology. It is also known that drugs blocking the P/Q- and N-type calcium channels have been successful in other animal models of trigeminovascular activation and head pain. In the present study, we used intravital microscopy to examine the effects of specific calcium channel blockers on neurogenic dural vasodilatation and calcitonin gene-related peptide (CGRP)-induced dilation. The L-type voltage-dependent calcium channel blocker calciseptine significantly attenuated (20 microg kg(-1), n=7) the dilation brought about by electrical stimulation, but did not effect CGRP-induced dural dilation. The P/Q-type voltage-dependent calcium channel blocker omega-agatoxin-IVA (20 microg kg-1, n=7) significantly attenuated the dilation brought about by electrical stimulation, but did not effect CGRP-induced dural dilation. The N-type voltage-dependent calcium channel blocker omega-conotoxin-GVIA (20 microg kg(-1), n=8 and 40 microg kg(-1), n=7) significantly attenuated the dilation brought about by electrical stimulation, but did not effect CGRP-induced dural dilation. It is thought that the P/Q-, N- and L-type calcium channels all exist presynaptically on trigeminovascular neurons, and blockade of these channels prevents CGRP release, and, therefore, dural blood vessel dilation. These data suggest that the P/Q-, N- and L-type calcium channels may be involved in trigeminovascular nociception.
在患有家族性偏瘫性偏头痛的患者中，发现了编码电压依赖性P/Q型钙通道α1A亚基的CACNA1A基因的错义突变。这表明钙通道病可能更广泛地参与偏头痛，并确立了遗传机制在偏头痛中的重要性。通道病与偏头痛有许多共同的临床特征，因此探索三叉神经血管系统中的钙通道功能可能有助于深入了解偏头痛的病理生理学。还已知阻断P/Q型和N型钙通道的药物在其他三叉神经血管激活和头痛的动物模型中取得了成功。在本研究中，我们使用活体显微镜检查特定钙通道阻滞剂对神经源性硬脑膜血管舒张和降钙素基因相关肽（CGRP）诱导的舒张的影响。L型电压依赖性钙通道阻滞剂钙阻滞肽显著减弱（20μg kg(-1)，n = 7）电刺激引起的舒张，但不影响CGRP诱导的硬脑膜舒张。P/Q型电压依赖性钙通道阻滞剂ω-芋螺毒素-IVA（20μg kg-1，n = 7）显著减弱电刺激引起的舒张，但不影响CGRP诱导的硬脑膜舒张。N型电压依赖性钙通道阻滞剂ω-芋螺毒素-GVIA（20μg kg(-1)，n = 8和40μg kg(-1)，n = 7）显著减弱电刺激引起的舒张，但不影响CGRP诱导 的硬脑膜舒张。据认为，P/Q型、N型和L型钙通道均存在于三叉神经血管神经元的突触前部位，阻断这些通道可防止CGRP释放，从而防止硬脑膜血管舒张。这些数据表明，P/Q型、N型和L型钙通道可能参与三叉神经血管伤害感受。
