BACKGROUND Migraine headaches affect more than 28 million persons in the United States (Foundation). Approximately 25% of women and 9% of men experience migraine headaches (Rasmussen BK, 1991) (Lipton RB, 1993) (Ramadan NM, 2002). Individuals with migraine headaches lose an average of 4 to 6 working days each year resulting in a total annual loss nationwide of 64 to 150 million workdays. It is estimated that the direct and indirect cost of migraines is nearly $17 billion (Hu XH, 1999) (RK., 1999). Headache is responsible for approximately 2% of all visits to emergency departments (Goldstein JN, 2006).

Migraine headaches are typically described as recurring, unilateral headache with untreated attacks lasting from 4 to 72 hours. The international headache Society Classification of Headaches list the following diagnostic requirements for migraine headache: at least two of the following features: your lateral location, throbbing character, worsening pain with routine activity, and moderate to severe intensity and at least one of the following features: nausea and/or vomiting and photophobia and phonophobia (Society, 1988).

TREATMENT There is no cure for migraine headaches. The treatments for migraine headaches are typically divided into non-pharmacologic and pharmacologic treatments. The non-pharmacologic treatments are designed to target those actions and behaviors known to trigger migraine headaches. The non-pharmacologic treatments include: regular sleep patterns, regular exercise, and the avoidance of known triggers. Triggers for migraine headaches can include: red wine, aged cheeses, exposure to chemical odors i.e. perfumes and cleaners. Non- pharmacologic therapies also include relaxation training, biofeedback, cognitive - behavioral therapy, hypnosis, transcutaneous electrical nerve stimulation, cervical manipulation, and hyperbaric oxygen.

The pharmacologic treatments for migraine headaches are typically divided into abortive therapies and prophylactic therapies. The abortive therapies are usually divided into nonspecific medications used to treat migraines: analgesics/NSAIDS (acetaminophen, aspirin, ibuprofen, naproxen sodium, ketorolac), and narcotic analgesics (meperidine and butorphanol), adjunctive therapy (metoclopramide, prochlorperazine). Migraine specific abortive therapies include ergotamine derivatives (ergotamine, caffeine plus ergotamine, dihydroergotamine) and the Triptans (Sumatriptan, Naratriptan, Rizatriptan, and Zolmitriptan) (Aukerman, 2002). Unlike the abortive therapies, which are taken to treat an existing headache, prophylactic therapies are taken (usually daily) to reduce the frequency and intensity of migraine headaches. Prophylatic, or preventive medications are generally divided into the first-line agents and second-line agents. First-line therapies for migraine prophylaxis in adults include propranolol (Inderal), timolol (Blocadren), amitriptyline, divalproex (Depakote), sodium valproate, and topiramate (Topamax) (Modi \& Lowder, 2006). Agents that could be used as second-line therapy for migraine prophylaxis in adults (listed by evidence of effectiveness) include gabapentin (Neurontin), naproxen (Naprosyn) or naproxen sodium (Anaprox), timed-release dihydroergotamine mesylate (DHE-45), candesartan (Atacand), lisinopril (Zestril), atenolol (Tenormin), metoprolol (Toprol XL), nadolol (Corgard), fluoxetine (Prozac), verapamil (Calan), magnesium, vitamin B2 (riboflavin), coenzyme Q10, hormone therapy (estradiol topical gel \[Estrogel\]), and botulinum toxin type A (Botox) injections (Modi \& Lowder, 2006).

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.

GLUCOSE METABOLISM AND MIGRAINE The relationship between migraine headaches and hunger is an accepted and well documented phenomenon. Missing meals can precipitate or trigger a migraine in susceptible individuals. Shaw et al., 1977 showed that migraine patients had impaired tolerance to glucose during migraine attacks compared with control studies. There was an elevation of plasma free fatty acid (FFA) levels during the migraine attacks. Growth hormone and cortisol were elevated and insulin was depressed during attacks. Patients with migraine have impaired insulin sensitivity (Rainero, et al., 2005). During the oral glucose tolerance test (OGTT), glucose plasma concentrations were significantly higher in migraineurs than in controls. Insulin sensitivity (measured by ISI-stumvoll and OGIS-180 indexes) was significantly altered in migraine. Cavestro et al. (2007) reported that headache patients had elevated blood glucose levels when compared to controls. They also documented that insulin levels were elevated in migraineurs when compared to control patients and other headache patients. Additional studies are needed to explore the role of impaired glucose metabolism in migraine including the role that glucose metabolism may play in the development of new therapies for migraine.

ROLE OF HISTAMINE IN MIGRAINE In 2003, Gazerani, et al. demonstrated a correlation between migraine, histamine, and immunoglobulin E. Serum samples were collected (for histamine levels and Immunoglobulin E levels) from 70 patients (18 - 58 years) with migraine during an attack and during remission and from 45 healthy volunteers. The migraine patients were divided into two groups according to their history of allergies (60% having a history of allergies and 40% without a history of allergies). Plasma histamine levels were significantly elevated (P ≤ 0.0001) in patients with migraine both during symptom-free periods (Error! Reference source not found.) and during migraine events (Error! Reference source not found.) when compared to the control group.

* RATIONALE FOR THE USE OF STUDY DRUG IN THE TREATMENT OF STUDY DISEASE In 1991, Guerrero, et al. carried out an initial study that provided evidence for the beneficial effects of histamine in migraine prophylaxis (Millan-Guerrero RO, 1999). Their data showed that subcutaneous administration of low doses (1-10 ng) of histamine induced significant relief from migraine symptoms, with no secondary effects. The possible mechanisms of histamine migraine prophylaxis, can be explained by histamine control of mast cells; the antidromic stimulation of trigeminal nerve endings induces the release of substance P and other neuromodulatory peptides, which in turn stimulate the release of histamine from mast cells. In meningeal blood vessels, activation of H1-receptors by histamine, results in vasodilatation and plasma protein extravasation, causing neurogenic inflammation (Akerman S, 2002). Krabbe and Olesen (Krabbe AA, 1980) and Lassen et al. (Lassen LH, 1995) showed that on migrainous subjects, intravenous administration of relatively high doses of histamine (0.5 mg/kg per minute for 20 min) caused an immediate headache during the infusion, followed by a delayed migraine attack which was abolished by pre-treatment with the H1-R antagonist, mepyramine. However, degranulation of mast cells and neuropeptide release from C fiber endings are inhibited by the histamine at low-concentration interaction with H3-receptors (H3-R), and probably reflects a local feedback circuit between C-fiber nerve endings and mast cells, which control neurogenic inflammation (Dimitriadou V, 1994) (Arrang J-M, 1983) (Arrang J-M G. M.-C., 1987) (Placeholder21). Guerrero, et al. proposed that the administration of low doses of histamine, to achieve and maintain low-circulating concentrations, may lead to a selective interaction of histamine with H3-R. Histamine could constitute a new therapeutic drug in migraine prophylaxis that acts by limiting the excessive inflammatory response involved in migraine pathophysiology.