Histamine in Migraine and Brain

Karl B. Alstadhaug, MD, PhD


Headache. 2014;54(2):246-259. 

In This Article

The Histamine Dynamics, Receptors, and Antihistamines in Migraine

Histamine has been extensively studied since it was isolated from the mould ergot a century ago.[89] It is synthesized from the amino acid L-histidine in one step by the enzyme L-HDC. Large systemic doses of L-histidine will raise the brain histamine concentration, but whether it triggers migraine is unknown. In the brain, histamine is almost exclusively metabolized by methylation, in the first hand carried out by the enzyme N-methyltransferase (HMT) producing N-methylhistamine. A polymorphism in the human HMT (Thr105Ile) is associated with decreased enzyme activity and presumed increased brain histamine levels. No increased prevalence of this gene variant was found in a study of migraine.[90] Systemically, histamine is metabolized by oxidation carried out by diamine oxidase (DAO). DAO is probably not constitutively expressed in the mammalian brain, but small amounts are detectable.[91] In the 1970s, Sjaastad and colleagues studied extensively the total turnover of histamine by assessing histamine and its catabolites in urine and whole blood of both migraineurs and patients with cluster headache.[37] The findings are difficult to interpret but, in short, a minor increase in turnover was found in cluster headache but not in migraine. However, the mean excretion of histamine in the urine was lower during attacks than during attack-free periods.[92]

Histamine acts through four metabotropic histamine receptors which are all G-protein-coupled (GPCR); H1R–H4R is pharmacologically active in only seconds, and the endogenous ligand has relatively low affinity to H1 and H2 receptors compared with the H3 and H4 receptors.[14,93–97] Some H2 receptor agonists and H3 ligands are also potent ligands for H4 receptor, but in general the antihistamines currently in clinical use (more than 45 H1 antihistamines are available) have probably little or no affinity for H3R and H4R.

H1 Receptors

H1Rs are widely distributed in the body, including the brain. Activation in the brain induces depolarizing responses in many areas, and functions like arousal, regulation of the sleep–wake cycle, memory and cognition are mainly mediated by this receptor. Studies where[3] H-pyrilamine (mepyramine) binding has been used to indicate, however, that a major portion of H1R actually may be associated with non-neuronal elements such as vessels and glia.[93] Histamine may for example serve as a signal for supply of more glucose from capillaries to astrocytes in the setting of increased synaptic activity.[98] It has been known for a long time that histamine may induce headache, and that both the blocking agent mepyramine and cimetidine (H2-blocker) may reduce and abolish histamine induced headache.[18] When H1R is stimulated in cranial arterial endothelium, nitric oxide synthase is activated with subsequent formation of NO and dilatation of the vessel.[99] In the mid-1990s, Olesen and colleagues formulated the "NO-hypothesis" as an explanation of why migraine is triggered; the primary event is a vasodilatation causing the throbbing headache.[100] They further assumed that the triggering mechanisms were mediated via the vascular H1 receptor.[16] However, a disturbing fact remained; neither H1- or H2-antihistamines had shown to be effective in treating migraine,[101] and the vascular changes in migraine are in many opinions a secondary response to neuronal activation.[5] The lack of effect of antihistamines must be interpreted with caution. If migraine pain results from binding to its receptors, one cannot expect an event that already has occurred to be blocked. Most of these old antihistamines are lipophilic compounds that readily penetrate into the brain, and clearly cause both anti-nausea and sedative effects. H1-receptor antagonists may therefore work well in treating associated symptoms of migraine, like nausea and vomiting, but also potentially damp cortical excitability. They are widely used in pregnant and pediatric patients,[102] and sometimes in combination with analgesics. Actually, two antihistamines (cinnarizine and cyproheptadine) that cross the BBB and cause sedation have been reported to be efficacious in preventing migraine.[103–105] Their efficacy has been ascribed by other actions than the antihistaminergic. Interestingly, meclizine, an antihistamine with a chemical structure similar to cinnarizine but with no effect on calcium channels, has not been rigorously tested in migraine, but favorable effects were reported in a case report in the 1950s.[106] To the best of our knowledge, no randomized controlled trial with first-generation H1-antihistamines in migraineurs with comorbid insomnia has been performed. More than 70% of CNS H1Rs are typically occupied after standard doses,[89] and side effects limit their potential use.

Alteration of brain histamine levels has also been shown to influence nociception in general, and both the H1 and H2 receptors are probably involved.[43] As acute medication for migraine, antihistamines have been studied as analgesia potentiators with mostly negative results.[107] In one study, the H1-antagonist hydroxyzine was compared to placebo. No effect was seen in migraine without aura, but a possible pain-relieving effect was suggested by the data in migraine with aura.[108]

H2 Receptors

Like H1R, H2 receptors are postsynaptic and potentiate excitatory inputs or mediate excitatory actions on neurons. H2R shows only about 40% homology with the H1R,[14] and much less is known of its effects in the CNS, partly because of limited available BBB penetrating H2 receptor antagonists. Experimental studies have shown that short exposure of the H2-agonist impromidine may cause enhanced firing of several types of neurons for hours.[14] Such enhanced and long-lasting responses may be seen in cortical neurons in response to a sensory stimulus, possibly through depolarization that has decisive influence on the thalamic relay of sensory input.[109] The prototypical H2 antagonist cimetidine, developed to suppress stomach acid secretion has shown ineffective as prophylaxis for both migraine and cluster headache.[110,111] Cimetidine, following systemic administration, only passes the BBB in very high doses,[112] and only peripheral actions of H2 antagonist have thus been evaluated in migraine.

H3 Receptors

Histamine has high affinity to the H3R and exerts GPCR signaling, but spontaneous signaling can also occur in the absence of endogenous histamine or other agonist, so-called constitutive receptor activity.[113] In contrast to the effects of H1 and H2 receptor activation, the H3R, which is located presynaptic both in the peripheral and central nervous system, shows low similarity to the H1R and H2R,[94] and promotes inhibitory actions on neurons. H3R causes autoinhibition of the histaminergic neurons themselves. Several isoforms that might have different pharmacological profiles exists, and there is evidence for genetic polymorphism within the human H3R. One, where the amino acid 280 (alanine) is substituted to valine, the H3RA280V variant, has been considered a risk factor for migraine.[114] The authors of the study suggested that increase histamine release due to increased population of inactive autoreceptors may be the cause, and in a recent study it was shown that the A280V variant actually reduces the signaling efficacy of the H3R.[115]

By modifying a side chain of the histamine imidazole molecule, selective and potent receptor agonists have been made, so-called (R)-α-methylhistamine compounds (RAMHs). Nα-methylhistamine is a histamine catabolite and an H3R agonist that is about 3 times more active than histamine.[14] It was reported safe and effective as prophylaxis in 18 patients with migraine in an open clinical trial.[116] Not surprisingly, the highest dose tested gave intense headache, probably due to the agonistic effect of H1 receptors. In a phase III study where 30 patients received Nα-methylhistamine subcutaneously twice a week for 12 weeks, the same research group found that it was superior to placebo.[117] This H3 receptor agonist does not cross the BBB.[118] Further, they showed that very low doses of histamine subcutaneous had effects similar to sodium valproate,[119] topiramate,[120] and botulinum toxin type A.[121] The authors ascribed the efficacy to reduced neurogenic inflammation and activation of C-fiber endings through inhibition of mast cells. Again only peripheral mechanisms were evaluated. The idea of giving low dose histamine or its catabolite, is to stimulate the H3 – feedback loop and cause reduced histamine release. The findings in these studies are somewhat surprising, considering that peripheral-acting antihistamines do not prevent against migraine. Centrally acting H3R agonists may also have potential as migraine prophylactic drugs. The RAMH prodrug SCH50971 penetrates the BBB, and is reported to both inhibit neurogenic inflammation in dura mater and to induce sleep.[122] Further, the RAMH immepip given intrathecally produced maximal antinociception in wild-type mice but not in mice lacking H3 receptors.[123] Both imidazole-containing and non-imidazole antagonists exist. These have been reviewed elsewhere,[118] and are not considered useful against migraine.

H4 Receptors

The H4 receptor, which shows considerable homology with the H3R (35%), is primarily localized in peripheral tissues and immune cells, including mast cells,[124] but was recently detected in the human cortex and several subcortical structures.[125] Its role in the CNS is largely unknown, but activation of H4R induces hyperpolarization in neurons of the mouse somatosensory cortex.[126] As mentioned, cortical hyperexcitability,[76] including the somatosensory cortex,[127] appears to be a fundamental feature of the migrainous brain.

The similarities between H3R and H4R, with overlap in pharmacological profiles, have made preclinical data difficult to interpret but analogous to the potential cortical excitability reducing effect by activating the H3R, the same effect may perhaps be achieved by stimulating the H4R. In a recent study, intracerebroventricular administration of an H4R agonist in the mouse induced acute thermal antinociception. By using the H4 receptor antagonist JNJ-10191584, this effect was prevented.[128] On the other hand, antinociceptive effect of a selective H4 receptor antagonist (JNJ-7777120) secondary to its anti-inflammatory actions has also been suggested.[129] It is worth noticing that several neuroactive drugs, including amitryptiline which is an effective migraine prophylactic drug,[130] bind to H4R.[97]

Future Perspectives

Alterations in the histaminergic system have been proposed in both neurological and psychiatric diseases, but to date, no specific disorder connected to a specific histaminergic dysfunction has been demonstrated. The role of peripheral acting histamine in migraine has been quite extensively explored, but its role as a potent modulator of meningeal nociceptors' activity in migraine is far from clear. Activation of inhibitory H3 receptors has previously been suggested for migraine prophylaxis. Low doses of subcutaneous histamine may theoretically be sufficient to stimulate sensitive H3 receptors, activating a negative feedback on histamine release from mast cells in proximity to C-fibers. Actually, three Class II single-center studies (performed by the same research group), one with N-alpha-methyl histamine and two with histamine, have established subcutaneous histamines as probably effective for migraine prevention.[131] However, its use is limited by an inconvenient treatment regime.

The role of the central histaminergic system in migraine is unexplored. At present, to predict the net effect of histamine in central networks seems quite impossible. However, both H3R and H4R ligands may theoretically have migraine prophylactic properties, but there seems to be a long and winding road before effective antihistaminergic treatment against migraine is established. Despite being promising drug targets for several diseases,[132] the lack of specificity and undesired side effects will probably be a major problem. A search across electronic databases[133] for ongoing studies on H3 and H4 receptor ligands in migraine or other types of headache was negative.

In general, incomplete understanding of the initial phase of the migraine attack is a major hindrance for the development of migraine prophylactic drugs. A deeper understanding of the chronobiology of migraine, the relationship to sleep and arousal, is needed. Preclinical studies exploring how hypothalamus may interact between the blood and brain to modulate thalamic and brain stem structures involved in migraine are probably the first key to unwind the etiology. This key may include histamine.