Topical review Deconstructing migraine headache into peripheral and central sensitization Rami Burstein * Department of Anesthesia and Critical Care, Beth Israel Deaconess Medical Center, Department of Neurobiology and the Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA Received 12 December 2000; accepted 13 December 2000 Migraine is a recurring neurological disorder commonly known as a throbbing unilateral head pain that is readily aggravated by routine physical activities. But the clinical de®nition of migraine includes a host of neurological symp- toms other than pain, namely, nausea, photophobia, phono- phobia, osmophobia, fatigue, and numerous disturbances in autonomic, mental, sensory and motor functions. The neural mechanisms underlying the development of migraine attacks are poorly understood. An attack can be precipitated by a wide variety of internal and external factors, including hormonal changes, psychosocial stress, certain foods, hunger, lack of sleep, excessive sleep, as well as by visual, auditory, olfactory or somatosensory stimulation. The potential of any of these factors to trigger a migraine attack appears to vary through complex interactions with the physiological milieu and individual genetic predisposition. For example, migraine attacks are more likely to develop during certain phases of the menstrual cycle (i.e. ovulation, menstruation), during certain phases of the sleep cycle (e.g. upon waking up), or in association with hunger. Candidate mechanisms to explain genetic predisposition towards migraine may include abnormal function of (a) receptor channels of sensory neurons in different cortical areas, (b) neurons regulating peripheral blood ¯ow and arterial resis- tance, (c) platelets or mast cells that chemically stimulate perivascular intracranial nerve ®bers. Based on the complexity of migraine and the intricacy of its physiologic and genetic origins, several alternative hypothesis have emerged regarding the initiation of the migraine pain: (a) activation of peripheral sensory ®bers that innervate intra- cranial blood vessels and the dura; (b) activation of descending pathways that facilitate processing of pain signals by spinal cord neurons; (c) suppression of descend- ing pathways that inhibit such processing of pain signals in the spinal cord. This review will focus primarily on the activation of the peripheral components because it is currently the only one supported by suf®cient scienti®c evidence. It will also summarize current understanding of the role that peripheral and central sensitization may play in the pathophysiology of migraine. The induction of headache following dural stimulation in awake patients (Pen®eld and McNaughton, 1940; Ray and Wolff, 1940) provided the ®rst evidence for the critical role that activation of peripheral sensory ®bers that innervate the dura play in migraine. Since then, many theories have been proposed regarding their activation during migraine (Goadsby and Edvinsson, 1993; Moskowitz and Macfar- lane, 1993). The most widely acknowledged theories proposed that the release of potassium and hydrogen ions in the vicinity of sensory ®bers that innervate the dura following transient disturbances in cortical sensory func- tions (Csiba et al., 1985; Scheller et al., 1992; Lauritzen, 1994; Mayevsky et al., 1996) could activate C-®ber menin- geal nociceptors, potassium ions through direct depolariza- tion, and hydrogen ions through the vallinoid receptor (Caterina et al., 1997) or acid-sensitive ion channel receptor (Waldmann et al., 1997). According to these theories, acti- vation of meningeal nociceptors could cause these sensory ®bers to secrete from their peripheral branches calcitonin- gene-related peptide (Ebersberger et al., 1999), a neuropep- tide capable of initiating neurogenic in¯ammation in the dura (Goadsby and Edvinsson, 1993; Moskowitz and Macfarlane, 1993) and the introduction of in¯ammatory agents such as histamine, serotonin, bradykinin and prosta- glandins to their environment. To test the potential contri- bution of these agents to the pain phase of the migraine attack, we recorded their impact on primary afferent neurons that innervate the meninges and on dorsal horn neurons that receive input from meningeal sensory ®bers, in our rat model. By analyzing response properties of individual meningeal primary afferent neurons in the trigeminal ganglion before, Pain 89 (2001) 107±110 0304-3959/01/$20.00 q 2001 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved. PII: S0304-3959(00)00478-4 www.elsevier.nl/locate/pain * Harvard Institutes of Medicine, Room 830, 77 Avenue Louis Pasteur, Boston, MA 02115, USA. Tel.: 11-617-667-0806; fax: 11-617-975-5329. E-mail address: rburstei@caregroup.harvard.edu (R. Burstein).