The Antimigraine Action of Arginine-Vasopressin: a Theoretical Basis

Keywords::

• arginine-vasopressin
• headache
• migraine
• migraine attack
• vomiting

Arginine-vasopressin hormone

Arginine-vasopressin (AVP), having a molecular weight of 1080, is a small peptide hormone comprised of nine amino acids in a ring structure. This neuropeptide hormone is also secreted by the posterior pituitary gland, which is synthesized in the hypothalamic supra-optic and the paraventricular nuclei. With regard to standard physiological conditions, AVP concentration in the plasma is little, which can cause difficulties in its measurement [1]. AVP has a number of roles in the body, including controlling water and electrolyte balance, managing effects of the vasomotor center and blood pressure, and regulating impacts on platelet aggregation and blood coagulation [2]. The main contribution of AVP is to multiply tubular reabsorption and to develop antidiuretic effects. It correspondingly adds to arterial blood pressure through atrial contraction. It should be noted that dehydration has been recognized as the most important stimulus for AVP release, leading to a rising trend in plasma osmolality levels. Considering identical variations in osmolality, sodium can also have a stronger influence on AVP secretion compared with glucose or urea [3].

AVP & migraine

Migraine is characterized as a phasic brain disorder, in which changes occur in subcortical aminergic sensory modulatory systems [4]. The most important feature of this condition is headache, though it has been associated with other symptoms, such as nausea, vomiting or photosensitivity [5,6]. AVP is the only peptide associated with vomiting and possibly moderate migraine pain. In this respect, vomiting has an antidiuretic effect, leading to an increase in AVP. Nausea alone, even without vomiting, is further related to a rapid and severe growth in AVP [5]. In response to stress and pain, metabolism, effectiveness and bioavailability of AVP are also clearly linked with migraine physiopathology [7]. The findings regarding AVP measurement in migraine have been thus far confusing. Accordingly, various studies have been conducted in this field, some have been inconsistent, but others have reported inhibited AVP secretion and increased urinary excretion as the most common findings, suggesting that changes in neuronal-electrical activity and neuropeptides in migraines may be associated with variations in the function of hypothalamus, subsequently leading to decreased AVP secretion [8,9]. Some migraine precipitators (namely stress, ethanol etc.) can also cause lowered AVP secretion and bioavailability, while some migraine-improving factors (e.g., tricyclic antidepressants, sleep etc.) can be associated with an elevation in AVP. On the other hand, there is some evidence, discarding the importance of AVP in migraines. For example, hypoglycemia, as a possible migraine trigger, can be assumed as a strong stimulant for AVP secretion. Chlorpromazine, which is also effective in treating migraine attacks, can further inhibit AVP release from the pituitary gland and may induce diuresis [10].

Studies on migraine & AVP in patients

Although AVP fails to contribute to migraine etiology, it plays a part in symptoms connected with migraine attacks. In this line, one study reported a decline in water-sodium clearance all through the early stage of migraine [11]. The results of another study, performed on 14 migraine patients, had further revealed a significant elevation in serum AVP concentration in the course of spontaneous migraine [12]. The levels of AVP produced in most patients was also sufficient to affect the kidneys. In a small number of patients, doses ranging from 5 to 10 pg/ml had been similarly found to be appropriate to alter blood circulation and facial pallor [12]. Administering intranasal AVP in one other study had correspondingly demonstrated that three puffs of AVP per nostril in a dose-dependent manner (with 100 ng, 200 ng or 400 ng AVP) lasting 3 h could relieve headaches [12]. The highest levels of AVP have been also seen in patients with vomiting, but an increase in AVP has been observed in patients who have even denied nausea [10]. Therefore, factors other than nausea are likely to play a role in boosting the levels of AVP. Another study had similarly suggested that a rise in AVP might occur during migraine attacks, possibly due to decreased fluid intake. In other words, an increase in AVP could be conditioned by this factor rather than by this fluid as a causative agent of migraine [13]. A rise in serum AVP levels during spontaneous migraines may be thus responsible for some manifestations of migraine attacks [12]. In one study, the impact of exogenous AVP on treatment of postlumbar puncture headache had been reported to be ineffective. Here, moderately induced migraine attacks associated with mild nausea had not augmented serum AVP concentrations. A rising trend in water and sodium clearance had been additionally observed during the recovery phase. To note, different AVP functions can be dose-dependent. The main role of AVP is also to maintain water balance through its effect on the kidneys. The maximal antidiuresis additionally occurs at serum concentrations of 1–3 pg/ml. At some point in certain stressors, such as severe nausea, vomiting and surgical procedure, serum AVP levels can temporarily reach 50 pg/ml [14]. In another study, six cases with a history of increased urinary frequency during migraines had been reported to be associated with severe diuresis and natriuresis and a significant decrease in urinary AVP [11].

AVP during migraine prodromal phase

The first phase in migraine attacks, namely prodrome, can potentially start hours or even days prior to other phases. While prodromal features are not the same, they might be uniform in an patient, presenting with sensitivity to light, odors and sound, as well as neck pain, drowsiness, fatigue and the like [15]. Activating AVP-related adaptive system can also enhance antinociception, as a process initiating in preprodromal and prodromal phases in the course of migraine attacks [16,17].

AVP during migraine attacks

The most debilitating part of migraine is the attack phase. Headaches often take place on one side of the head and transfer to other parts during this condition [5]. Studies in this respect have indicated a significant association between lowered urinary concentration of AVP and urine volume and urinary sodium in migraine patients during such attacks. However, such an association has not been observed between attacks [11,18,19]. According to previous studies, regulation of water excretion in the kidneys and the peripheral blood flow through AVP occurs only in patients who have vomited during migraine attacks [11], which may be directly due to hypovolemia. Thus, vomiting is a stimulant for AVP secretion by itself, as the only peptide connected with vomiting and possibly mitigation of migraine pain. It is of note that vomiting has an antidiuretic effect, leading to an increase in AVP. Nausea alone, even without vomiting, can be further associated with a rapid and severe elevation in AVP [20]. In this regard, one study had found that AVP receptors on platelets had amplified in migraine attacks, indicating a rising trend in platelet sensitivity to AVP under such conditions. Therefore, further attention should be given to controlling migraines via AVP [21–23]. AVP at serum concentrations higher than 100 pg/ml, which are larger than the range to achieve maximum antidiuretic capacity, may also have effects on blood pressure, cutaneous circulation, coagulation, fibrinolysis, as well as blood glucose levels.

AVP during postdrome phase

Postdrome has still not been defined in the International Classification of Headache Disorders and even prospectively documented [24]. The symptoms of postdrome may be fatigue, depression, lower levels of intellect, feelings of euphoria and well-being, as well as deficiency in concentration/comprehension [24]. It is unclear why AVP doses exceed the required maximum renal function. Migraine is also sometimes associated with delayed diuretic phase, facial pallor and platelet disorders; however, the role of AVP in these events is unclear [25]. The effect of AVP and coagulation also occurs at concentrations of 15–20 pg/ml in a dose-dependent manner [26]. Facial pallor and coagulation abnormalities reported during migraine recovery phase may be correspondingly related to high serum AVP levels [27]. Nevertheless, the place of AVP in medicating these effects has not been thus far investigated. As mentioned, migraines are sometimes linked with diuresis (particularly during the recovery phase), facial pallor and platelet dysfunction.

In this line, researchers believe that increased AVP levels are sufficient to induce antidiuresis in most patients and to develop extrarenal complications in a few individuals. However, such a view cannot be justified in the following situations:

• Decreased AVP expression at the early stages of migraine headaches has been shown to be associated with elevated urinary frequency.

• Controlling headaches by developing diuresis at the early stages of migraines has thus far failed.

• Most patients with migraine have demonstrated no changes in the frequency of urination or symptoms of fluid retention during migraines.

• Prodromal phase may take several hours to several days, in which confounding AVP plasma levels can be established.

In some studies, a significant reduction in migraine pain paroxysms following AVP administration has highlighted the importance of its beneficial function. The present commentary does not generally suggest the role of AVP as a therapeutic innovation but reinforces the idea of the contribution of AVP in migraines.

Vasoconstrictor agents in migraine

The underlying logic of using AVP in migraines is consistent with the principles of other vasoconstrictor agents administered as a treatment for migraines, including serotonin. Hyperfunction of the sympathetic nervous system, along with increased access to AVP and serotonin during a migraine attack, may thus form an endogenous vasomotor adaptive system [28]. Onset can be also considered as the fatigue of this system, which is in the form of antidromic discharges of trigeminal nerves. The most common cause of migraine is stress. Adrenocorticotropic activity is also regarded as one of the basic defense mechanisms in stress. Besides, AVP potentiates the effects of corticotropin-releasing hormone on adrenocorticotropic hormone secretion. AVP and glucocorticoids have been further confirmed to have antagonistic effects on water excretion, while dopamine has been documented to cause diuresis during migraines through inhibiting AVP release [5]. Therefore, careful adjustment of two factors with opposite effects on sodium and water balance in renal tubules (that is, AVP and cortisol via increased reabsorption of water and electrolytes as well as antagonists such as endogenous opioid peptide, dopamine and atrial natriuretic peptide, inhibiting AVP release) may cause proper water homeostasis in most migraine patients [12,29]. AVP, calcitonin and somatostatin have been correspondingly shown to have antinociceptive effects.

Conclusion

Inhibited AVP secretion and augmented urinary excretion have been thus far established as the most common findings about migraines. As one component of the adaptive system that is able to delay or abort migraine attacks, AVP also promotes vasomotor center control, antinociception and behavior. As a whole, numerous manifestations of migraine can be associated with variations of AVP metabolism, which are not primary but are secondary reactive or adaptive responses that can slow down the onset of headaches.

Future perspective

Adopting a multidisciplinary approach integrating the findings of evolving biochemical, genetic and pharmacological studies with imaging techniques is regarded as the best strategy to recognize and care for migraine. Accordingly, future studies should reflect on identification of biomarkers predicting theraputic responses. Signaling in migraine can be also blocked in various ways. Monoclonal antibodies or small molecules can even target signaling pathways although effective pathways associated with migraine treatment have remained unspecified. Translational medicine has thus conveyed this basic science research data to human science, establishing an experimental human migraine model and raising novel insights on vascular mechanics as well as neuro-imaging studies.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.