Headache is among the most common reasons patients seek medical attention, on a global basis being responsible for more disability than any other neurologic problem. Diagnosis and management are based on a careful clinical approach augmented by an understanding of the anatomy, physiology, and pharmacology of the nervous system pathways mediating the various headache syndromes. (1) The first and most important consideration in evaluating patients with complaints of orofacial pain or headache is to rule out an underlying progressive structural lesion or systemic diseases, such as intracranial tumors, severe infection, aneurysms, hypertension, and stroke. Headache is generally a benign symptom, but it is estimated that 5% of patients with headache in emergency settings are found to have a serious underlying disorder, emphasizing the need for rapid and accurate diagnosis of headache.(2)
Migraine is a common disabling primary headache disorder. It is estimated that the prevalence of migraine headaches in adults with current headache disorder, at least once last year from symptoms is 47%. Half to three-quarters of adults between the ages of 18 and 65 in the world had headaches last year, and more than 10 percent of them reported migraines (3). Migraines are common especially during adolescence, and in women of childbearing age but this is occurred as most prevalent childhood headache (4). An analysis from the 2016 Global Burden of Disease (GBD) study, including data from 132 countries, estimated that worldwide 1.04 billion people had migraine, corresponding to a prevalence of 14.4% overall, 18.9% in women, and 9.8% in men.(5) The core features of migraine are headache, which is usually throbbing and often unilateral, and associated features of nausea, sensitivity to light, sound, and exacerbation. Clinically, migraine is categorized into five categories include: Migraine without aura (common migraine), Migraine with aura (classic migraine), chronic migraine (CM), episodic migraine (EM) and probable migraine headaches. (6)
In common migraines or migraine without aura, there are no focal neurological symptoms before the headache. In migraine with aura, the headache is preceded by stereotyped sensory, motor, or visual symptoms. The most common premonitory symptoms in migraine include visual scotomas and fortification spectra, and approximately one third of all migraineurs are affected. (7) CM defined as experiencing more than 15 days of headache per month with at least 8 days with migraine characteristics or response to Triptans, for at least 3 months and episodic migraine (EM) defined as having less than 15 days of migraine headache per month (8). If EM patients do not receive proper treatment, their headaches can progress to CM over time. In comparison with EM sufferers, subjects with CM experience greater headache-related disability. (9) Migraine frequency varies considerably. In many patients, migraine is triggered by specific factors, such as menses, weather changes, irregular sleep, alcohol, or certain foods. Migraine is also often relieved by sleep.(10)
Many mechanisms and theories explaining the causes of migraine have been
proposed, although the full picture is still elusive. A strong familial association and the early onset of the disorder suggest a genetic component, which has led some to question whether it is a channelopathy. There appears to be a genetic and familial risk as more than half of all migraineurs report having other family members who suffer from migraine. In addition, specific mutations leading to rare causes of vascular headache have been identified. Some researchers suggests that variations within the dopamine D2 receptor gene also may have some effect on susceptibility to migraine. (11, 12) The trigeminal vascular model by Moskowitz explains that trigeminal activation resulting in the release of neuropeptides produces neurogenic inflammation, increased vascular permeability, and dilation of blood vessels.(13) Other pathophysiologic mechanisms behind migraine have been proposed, such as serotonin, calcitonin gene-related peptide, nitric oxide, dopamine, norepinephrine, glutamate, and other substances as well as mitochondrial dysfunction. (13–16) It has recently been recognized that central sensitization producing allodynia and hyperalgesia is an important clinical manifestation of migraine.(17, 18)
The aura of migraine was once thought to be caused by cerebral vasoconstriction and the headache by reactive vasodilation, which explained the throbbing quality of migraine and the relief of pain by ergots. Some cerebral blood flow changes do occur in aura, however, migraine without aura demonstrates no flow abnormalities; thus, it is unlikely that simple vasoconstriction and vasodilation are the fundamental pathophysiologic feature. (19, 20)
Recent studies have identified specific substances and receptors with potential roles in nociception that provide therapeutic targets, including substance P, calcitonin gene related peptide (CGRP), glutamate, serotonin, vanilloid receptor and NMDA receptor. (21) These neuropeptides and other cytokines interact with the blood vessel wall to produce dilation, plasma protein extravasation, and platelet activation producing a sterile inflammation that activates trigeminal nerve nociceptive afferents leading to further pain production.(22)
CGRP was first reported in 1982. This peptide are found in two types, alpha and beta. CGRP I or α-CGRP is a 37-amino acid neuropeptide and is formed from the alternative splicing of the calcitonin/CGRP gene located on chromosome 11. CGRP II or β-CGRP is less studied. In humans, β-CGRP differs from the α-CGRP by three amino acids and is encoded in a separate gene within the same vicinity. CGRP has a distribution in both operation and receptor type, with 4 different receptor types reported for this peptide so far. This peptide can also act as a neurotransmitter, or a local hormone, or a neurodegenerator, which can have a variety of effects on different tissues (23).
CGRP levels increase in the cranial circulation during migraine attacks, and GRP injection in migraineurs results in migraine-like attacks. The somatosensory function of CGRP has been implicated in the development of neuronal sensitization and pain generation, most notably in migraine. Considerable evidence points towards CGRP as a key player in migraine pathogenesis: (a) CGRP is a potent vasodilator, and is present in afferents innervating meningeal blood vessels; (b) CGRP is a neurotransmitter that can enhance synaptic transmission mediated by glutamatergic signaling; (c) Elevations of CGRP can be detected in jugular venous blood during migraine attacks; (d) Intravenous injection of CGRP triggers migraine in patients with migraine, but not in healthy volunteers. (24–26)
The role of CGRP in migraine pathophysiology has gained considerable interest in recent years. This led to the development of small molecule CGRP receptor antagonists for acute and preventive treatment of migraine and monoclonal antibodies against CGRP mechanisms for migraine prevention. (27) Ziegler and Hassanein found that 44% of patients diagnosed as having migraine with aura reported having had an aura occur without a headache at some time.(28) Mattsson and Lundberg compared 100 women with migraines in a headache clinic in Sweden with 245 women in the general population and found that the lifetime prevalence of visual disturbances without a headache was 37% in those with migraines and 13% in the general population. Undoubtedly, some of those in the general population had migraines as well.(29) Peripherally administered CGRP induces spontaneous pain in mice. Brandon J. Rea et al report that peripherally administered CGRP can act in a light-independent manner to produce spontaneous pain in mice that is manifested as a facial grimace. As an objective validation of the orbital tightening action unit of the grimace response, we developed a squint assay using a video-based measurement of the eyelid fissure, which confirmed a significant squint response after CGRP injection, both in complete darkness and very bright light. (30) Despite many studies occurred about CGRP in migraine headaches, the exact pathways involved in CGRP-induced migraine attacks and mechanisms of action of CGRP antagonists are largely unknown (31). According to our researches, evaluation and comparison between migrainous group according to aura and their clinical variation such as severity, duration, frequency of attacks, weight, didn’t published.
The present study aim to investigate serum CGRP level in participants of three groups of this study: healthy control, migraine with aura and migraine without aura by using ELISA methods and also define its concentration in relation to clinical and features.