Histamine and migraine revisited: mechanisms and possible drug targets

Abstract

ObjectiveTo 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.BackgroundHistamine 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.MethodsFor 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.FindingsEarly 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 Nα-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.ConclusionThere 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.

Histamine Intolerance: The Current State of the Art

“…Functionally, this amine is involved in various immune and physiological mechanisms, stimulating gastric acid secretion, inflammation, smooth muscle cell contraction, vasodilation and cytokine production, among other processes [ 8 , 9 , 10 , 11 ]. In addition, histamine functions as a neurotransmitter, being synthesized by neurons located in the posterior region of the hypothalamus whose axons extend through the brain [ 12 ]. These wide-ranging physiological effects occur by interaction with four G-protein-coupled receptors with seven transmembrane domains (H1, H2, H3 and H4), which activate signal transduction pathways upon perceiving their ligand, histamine [ 7 , 12 ].…”

“…In addition, histamine functions as a neurotransmitter, being synthesized by neurons located in the posterior region of the hypothalamus whose axons extend through the brain [ 12 ]. These wide-ranging physiological effects occur by interaction with four G-protein-coupled receptors with seven transmembrane domains (H1, H2, H3 and H4), which activate signal transduction pathways upon perceiving their ligand, histamine [ 7 , 12 ].…”

Enigmatic Histamine Receptor H4 for Potential Treatment of Multiple Inflammatory, Autoimmune, and Related Diseases

“…However, in the last two decades, there was a particular increment in evidence supporting participation of H 3 R and H 4 R in neuropathic pain modulation [1]. Histamine has also been identified to be responsible for a vascular type headache, e.g., migraine, hence the antihistamines are regarded as a possible treatment [2]. The proper action of particular subtypes of histamine receptors is of special importance as it has been shown for instance for the delirium syndrome in which H 1 R and H 2 R antagonists have pro-delirium potential, while H 3 R antagonists have proved to be beneficial in combating delirium.…”

The Effects of SJP-001 on Alcohol Hangover Severity: A Pilot Study

“…In addition, alcohol and acetaldehyde liberate histamine from mast cells and depress histamine elimination by inhibiting diamine oxidase [31]. Independently of alcohol consumption, prostaglandin and histamine release contributes to inflammation, pain (including headache), and fatigue [32][33][34]. These are all symptoms of alcohol hangover [5,6].…”