PATHOGENESIS OF MIGRAINE Despite extensive research in the area of migraine headaches, the precise pathogenesis of migraine remains unknown. The list of potential candidates for the pathogenesis of migraines is extensive. For many years the excepted pathogenesis of migraine headaches was that they were due to extracerebral vasodilation. This theory proposes that the auras associated with migraine headache were due to an initial vasoconstriction which is followed by a vasodilatation of extracerebral vessels which resulted in the pain of a migraine headache. Others (Blau, 1984) have proposed that migraine is a primary neurological disturbance with secondary vasomotor changes. Migraine is likely a multi-genic condition with a complex pathophysiology in which both central and peripheral components of trigeminal pain pathway play a role in the signs and symptoms. In the past two decades the trigeminal vascular system (TVS) has been proposed as a possible component of migraine attacks. Nitric oxide has also been proposed as a potential mechanism for migraines, supported by the production of typical migraine headaches in migraneurs treated with nitroglycerin (NTG). 5-hydroooxytryptamine (5-HT) has been implicated in migraine pathophysiology. The role for 5-HT metabolism in migraine is supported by a low central 5-HT disposition associated with increase in 5-HT release during an attack (Panconesi, 2008). Weir and Cader (2011) have proposed that channelopaties may play a role in migraine headaches, especially those with a genetic association. Cortical spreading depression has been implicated as a cause for migraine aura (Weir 2011). The Neurogenic inflammation (NI) theory proposes that, vasodilation and plasma protein extravasation in tissue receiving trigeminal innervation occurs when vasoactive peptides are released from nerve endings (Buzzi, 2005). Burstein, et al., 2011 has proposed that peripheral sensitization is a major contributor to hypersensitivity in many painful syndromes including migraine headaches. In this state primary afferent nociceptive neurons exhibit increased responsiveness to external stimuli at the original site of inflammation or injury. A large number of chemical mediators produced at a site of inflammation or tissue injury can promote excitation and sensitization of nociceptors. These chemical mediators include bradykinin, histamine, serotonin (5-HT), and prostaglandins. Cytokines (interleukins 1, 6 and 8 [IL-1, IL-6, IL-8] and tumor necrosis factor alpha [TNF-alpha]) are inflammatory mediators known to promote peripheral sensitization (Burstein, et al., 2011). Central sensitization which occurs in two distinct phases, the initiation phase and the maintenance phase may play a role in migraine headache. This sensitization is mediated by the excitatory amino acid glutamate and neuropeptides such as substance P and neurotrophic factors. The enhanced neuronal excitability in central sensitization involves the phosphorylation of intracellular and extracellular kinases and the enhanced production of cyclooxygenase. The list of chemical mediators involved in the pathogenesis of migraine is extensive. The scientific investigations required to elucidate the exact mechanisms responsible for migraine headaches continues as an important part of ongoing clinical trials.