Histamine and migraine revisited: mechanisms and possible drug targets

Abstract

Objective: To review the existing literature on histamine and migraine with a focus on the molecule, its receptors, its use in inducing migraine, and antihistamines in the treatment of migraine.

Background: Histamine has been known to cause a vascular type headache for almost a hundred years. Research has focused on antihistamines as a possible treatment and histamine as a migraine provoking agent but there has been little interest in this field for the last 25 years. In recent years two additional histamine (H₃ and H₄) receptors have been discovered and a series of non-sedating antihistamines have been developed. It is therefore timely to review the field again.

Methods: For this review the PubMed/MEDLINE database was searched for eligible studies. We searched carefully for all articles on histamine, antihistamines and histamine receptors in relation to migraine and the nervous system. The following search terms were used: histamine, migraine disorders, migraine, headache, antihistamines, histamine antagonists, clinical trials, induced headache, histamine H₃ receptor, histamine H₄ receptor and pharmacology. Four hundred thirty-six titles were read, 135 abstracts were read, 112 articles were read in full and 53 articles were used in this review. Review process resulted in 12 articles added to a total of 65.

Findings: Early studies of H₁ and H₂ antihistamines lack scientific strength and show conflicting results. Most of the antihistaminic drugs used in these trials bind also to other receptors which makes it difficult to conclude on the antihistaminic effect. Histamine is an efficient inducer of migraine attacks in migraine patients by an H₁ mechanism most likely extracerebrally. These findings merit further investigation of antihistamines in clinical drug trials. The H₃ and H₄ receptors are found in primarily in CNS and immune tissues, respectively. H₃ is likely to be involved in antinociception and has been linked with cognitive, neurodegenerative and sleep disorders. The only marketed H₃ agent, pitolisant, is a brain penetrant H₃ antagonist/inverse agonist which increases central histamine and causes headache. The experimental H₃ agonist N^α-methylhistamine has shown promising results as a migraine preventative in studies of uncertain quality. With the current limited knowledge of the H₄ receptor it is questionable whether or not the receptor is involved in migraine.

Conclusion: There is insufficient support for first generation antihistamines (both H₁ and H₂) as preventive migraine medications and sedation and weight gain are unacceptable side effects. Non-sedating H₁ antihistamines need to be appropriately tested. Central H₃ receptors seem to have a role in migraine that merit further investigation. The histaminergic system may be a goal for novel migraine drugs.

Keywords: Antihistamines; Drug targets; Histamine; Histamine receptors; Migraine.

Fig. 1

Historical timeline of histamine and its receptors. Reprinted from (11) Copyright© 2011 with permission from Elsevier, J Allergy Clin Immunol

Fig. 2

Neuronal H3 receptors are located on both histaminergic (brown) and non-histaminergic neurons (arrows). On histaminergic neurons H3 acts as an autoreceptor inhibiting the release of histamine itself. The figure shows the complex distribution of H₃ receptors that emphasizes the challenge of predicting the effects mediated by H₃ receptors. Reprinted from (12) Copyright© 2015 with permission from ASPET, Pharmacol Rev.

Fig. 3

Downstream signaling from the H3 receptor. Opposite to the H₂ receptor, adenylate cyclase is inhibited by the H₃ receptor. Reprinted from (13) Copyright© 2016 with permission from ASPET, Mol Pharmacol

Fig. 4

Structural formula of pitolisant