Orexin 1 receptor activation attenuates neurogenic dural vasodilation in an animal model of trigeminovascular nociception
Orexin 1 receptor activation attenuates neurogenic dural vasodilation in an animal model of trigeminovascular nociception
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DOI：
10.1124/jpet.105.090951
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发表时间：
2005-12-01
影响因子：
3.5
通讯作者：
Goadsby, PJ
中科院分区：
文献类型：
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作者：
Holland, PR;Akerman, S;Goadsby, PJ
尽管含有感觉神经肽降钙素基因相关肽（CGRP）的三叉神经血管传入一定有一定的作用，但偏头痛发作时搏动性疼痛的病理生理机制尚不完全清楚。抗偏头痛药物，如曲坦类药物，5-羟色胺（1B/1D）受体激动剂，可重复地阻断与CGRP释放相关的神经源性血管舒张。我们研究了下丘脑神经肽orexin A和orexin B对神经源性硬脑膜血管舒张的影响，并分析了新型orexin 1 （OX1）受体拮抗剂N-（2-甲基-6-苯并恶唑）-N"-1,5-萘啶脲（SB-334867）的受体药理学。电刺激硬脑膜传入（50-300 μ A）可导致136 +/- 9%的再现性硬脑膜血管扩张。Orexin A 30 μ g kg(-1), 3 μ g kg（-1）和10 μ g kg（-1）对电刺激引起的舒张的抑制作用为60%，15 min后最大(t(7) = 7.138；P < 0.001；N = 8)。用OX 1受体拮抗剂SB-334867预处理后，这种反应被逆转。在食欲素A的最大作用点添加CGRP(8-37)，与只添加食欲素A相比，神经源性硬脑膜血管舒张进一步显著降低。CGRP给药（1 μ g kg(-1)）可产生可重复的硬脑膜血管扩张145 = 7%，静脉给药（30 μ g kg(-1)）不受抑制。即使在最高剂量下，食欲素B也没有明显的效果。目前的研究表明，食欲素A能够通过激活OX1受体来抑制神经源性硬脑膜血管舒张，从而抑制三叉神经神经元的CGRP的突触前释放。
The pathophysiology underlying the pulsating quality of the pain of a migraine attack is not fully understood, although trigeminal vascular afferents containing the sensory neuropeptide calcitonin gene-related peptide ( CGRP) must have a role. Antimigraine drugs, such as triptans, serotonin 5-hydroxytryptamine(1B/1D) receptor agonists, reproducibly block neurogenic vasodilation associated with CGRP release. We examined the effects of the hypothalamic neuropeptides orexin A and orexin B on neurogenic dural vasodilation, dissecting out the receptor pharmacology with the novel orexin 1 (OX1) receptor antagonist N-(2-methyl-6-benzoxazolyl)-N"-1,5-naphthyridin4-yl urea (SB-334867). Electrical stimulation of dural afferents (50-300 mu A) resulted in reproducible dural vasodilation of 136 +/- 9%. Orexin A 30 mu g kg(-1), but not 3 and 10 mu g kg(-1), inhibited the dilation brought about by electrical stimulation over 60 min and maximally after 15 min by 60% (t(7) = 7.138; P < 0.001; n = 8). This response was reversed by pretreatment with the OX 1 receptor antagonist SB-334867. Addition of CGRP(8-37) at the point of maximal effect of orexin A produced a further significant decrease in neurogenic dural vasodilation compared with orexin A only. CGRP administration (1 mu g kg(-1)) produced a reproducible dural blood vessel dilation of 145 = 7% that was not inhibited by intravenous administration of orexin A (30 mu g kg(-1)). Orexin B had no significant effect even at the highest dose. The current study demonstrates that orexin A is able to inhibit neurogenic dural vasodilation via activation of the OX1 receptor, resulting in inhibition of prejunctional release of CGRP from trigeminal neurons.