Johnson K W, Phebus L A, Cohen M L
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Prog Drug Res. 1998;51:219-44. doi: 10.1007/978-3-0348-8845-5_6.
A role for serotonin in migraine has been supported by changes in circulating levels of serotonin and its metabolites during the phases of a migraine attack, along with the ability of serotonin-releasing agents to induce migraine-like symptoms. The development of serotonin receptor agonists with efficacy in the clinic for the alleviation of migraine pain further implicates serotonin as a key molecule in migraine. Several theories regarding the etiology of migraine have been proposed. The vasodilatory theory of migraine suggested that extracranial arterial dilation during an attack was related to migraine pain; a theory supported when vasoconstrictors such as sumatriptan alleviated migraine pain. The neurological theory of migraine proposed that migraine resulted from abnormal firing in brain neurons. Cortical spreading depression, one facet of the neurological theory, could explain the prodrome of migraine. The neurogenic dural inflammation theory of migraine supposed that the dural membrane surrounding the brain became inflamed and hypersensitive due to release of neuropeptides from primary sensory nerve terminals. Substance P, calcitonin gene related peptide and nitric oxide are all though to play a role in the dural inflammatory cascade. Animal models of migraine have been utilized to study the physiology of migraine and develop new pharmaceutical therapies. One model measures the shunting of blood to arteriovenous anastomoses based on a proposal that migraine primarily involves cranial arteriovenous vasodilation. Another model utilizes electrical stimulation of the trigeminal ganglion to induce neurogenic dural inflammation quantified by the resulting extravasation of proteins. Pharmacological agents such as meta-chlorophenylpiperazine (mCPP) and nitroglycerin have also been used to induce dural extravasation in animals. Both compounds also induce migraine attacks in individuals with a history of migraine. In addition, Fos, a protein produced by activation of the c-fos gene, has been measured as an index of migraine-like pain transmission to the CNS following chemical or electrical stimulation of the trigeminal nerve. A role for serotonin in migraine is further supported by the efficacy of serotonin receptor ligands. Sumatriptan is an agonist at 5-HT1D and 5-HT1B receptor subtypes, and effective in treating migraine pain and associated symptoms. Recently, selective 5-HT1F agonists have been proposed for the treatment of migraine, without the side effects associated with the present 5-HT1D and 5-HT1B receptor agonists. A role for 5-HT2B receptors has also been suggested the initiation of migraine, supporting use of selective 5-HT2B receptor antagonists in migraine. Thus, agents that modulate 5-HT1B, 5-HT1D, 5-HT1F and 5-HT2B receptors either have or may have clinical utility in the therapy of migraine headache.
血清素在偏头痛中的作用已得到偏头痛发作各阶段血清素及其代谢物循环水平变化的支持，以及血清素释放剂诱发偏头痛样症状的能力的支持。临床上有效缓解偏头痛疼痛的血清素受体激动剂的开发进一步表明血清素是偏头痛的关键分子。关于偏头痛病因的几种理论已被提出。偏头痛的血管舒张理论认为，发作期间颅外动脉扩张与偏头痛疼痛有关；当舒马曲坦等血管收缩剂缓解偏头痛疼痛时，这一理论得到了支持。偏头痛的神经学理论提出，偏头痛是由脑神经元异常放电引起的。神经学理论的一个方面——皮层扩散性抑制，可以解释偏头痛的前驱症状。偏头痛的神经源性硬脑膜炎症理论认为，由于初级感觉神经末梢释放神经肽，围绕大脑的硬脑膜会发炎并变得超敏。P物质、降钙素基因相关肽和一氧化氮都被认为在硬脑膜炎症级联反应中起作用。偏头痛的动物模型已被用于研究偏头痛的生理学并开发新的药物疗法。一种模型根据偏头痛主要涉及颅动静脉血管舒张的提议来测量血液向动静脉吻合处的分流。另一种模型利用三叉神经节的电刺激来诱发神经源性硬脑膜炎症，并通过由此产生的蛋白质外渗来量化。像间氯苯哌嗪（mCPP）和硝酸甘油这样的药物也被用于诱导动物硬脑膜外渗。这两种化合物也会在有偏头痛病史的个体中诱发偏头痛发作。此外，Fos是一种由c-fos基因激活产生的蛋白质，已被测量作为三叉神经化学或电刺激后偏头痛样疼痛向中枢神经系统传递的指标。血清素受体配体的疗效进一步支持了血清素在偏头痛中的作用。舒马曲坦是5-HT1D和5-HT1B受体亚型的激动剂，对治疗偏头痛疼痛及相关症状有效。最近，选择性5-HT1F激动剂已被提议用于治疗偏头痛，而没有目前5-HT1D和5-HT1B受体激动剂相关的副作用。5-HT2B受体在偏头痛发作中的作用也已被提出，这支持了在偏头痛中使用选择性5-HT2B受体拮抗剂。因此，调节5-HT1B、5-HT1D、5-HT1F和5-HT2B受体的药物在偏头痛性头痛的治疗中已经或可能具有临床应用价值。
