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Ferretti, A.; Gatto, M.; Velardi, M.; Di Nardo, G.; Foiadelli, T.; Terrin, G.; Cecili, M.; Raucci, U.; Valeriani, M.; Parisi, P. Role of the Histaminergic System in Migraines. Encyclopedia. Available online: (accessed on 20 June 2024).
Ferretti A, Gatto M, Velardi M, Di Nardo G, Foiadelli T, Terrin G, et al. Role of the Histaminergic System in Migraines. Encyclopedia. Available at: Accessed June 20, 2024.
Ferretti, Alessandro, Mattia Gatto, Margherita Velardi, Giovanni Di Nardo, Thomas Foiadelli, Gianluca Terrin, Manuela Cecili, Umberto Raucci, Massimiliano Valeriani, Pasquale Parisi. "Role of the Histaminergic System in Migraines" Encyclopedia, (accessed June 20, 2024).
Ferretti, A., Gatto, M., Velardi, M., Di Nardo, G., Foiadelli, T., Terrin, G., Cecili, M., Raucci, U., Valeriani, M., & Parisi, P. (2023, May 23). Role of the Histaminergic System in Migraines. In Encyclopedia.
Ferretti, Alessandro, et al. "Role of the Histaminergic System in Migraines." Encyclopedia. Web. 23 May, 2023.
Role of the Histaminergic System in Migraines

The histaminergic system may play an important role in migraine pathophysiology, and dietary histamine, similar to other chemical dietary triggers, may play a role in some individuals suffering from migraines.

histaminergic system nociception histamine migraine

1. Histamine and the Central Nervous System

It had been proved that the continuous intravenous infusion of histamine could elicit a headache [1]. This effect is consistent with the hypothesis of mast cells, immunoglobulin E, histamine, and cytokines [2] playing mediating roles in migraine pathways. Histaminergic fibers are represented in the migraine-related neural structures [3], and several studies have documented higher levels of histamine and IgE in patients suffering from migraines compared with controls [4][5]. Histamine, a diamine linked to gastric secretion, mast cells, and the immune system [2], has an important function as a neurotransmitter in the CNS [6]. Histaminergic neurons originate from the tuberomammillary nucleus (TMN) of the posterior hypothalamus [3], which projects to a suprachiasmatic nucleus (SCN) [7][8] of the hypothalamus itself. The histamine released from the TMN helps to modulate the circadian rhythm, the sleep–wake cycle, pituitary hormone secretion, thermoregulation, energy expenditure, and food intake [2][9]. During wakefulness, its activation is variable; however, during somnolence and sleep, it is no longer activated through gamma-aminobutyric acid connections [10]. The extracellular levels of histamine in the preoptic/anterior hypothalamus follow the oscillations of the different sleep phases (wake > non-REM sleep > REM sleep) [10], providing further evidence of the importance of histamine in circadian regulation [11]. The close correlation between the regulation of circadian rhythms and migraines [12] has also been confirmed through migraine mouse model studies, which have suggested an inadequate coping mechanism compared to that of the general population as a possible cause [13]. The pain response and modulation of headache attacks are other histamine-mediated hypothalamic functions [11][14]. Rat studies have demonstrated strict connections between the TMN, thalamic nuclei, and the trigeminal output, indicating that histamine may trigger headache stressors involved in the perception of whole-body allodynia (abnormal skin sensitivity) and photophobia (abnormal sensitivity to light) during migraine [15][16]. The histaminergic system is also connected with the trigeminal vascular system, known to be involved in migraine pathophysiology [17][18][19], and with orexinergic, noradrenergic, and serotonergic areas [6][11]. For these reasons, it plays a role in a wide range of cognitive functions and acts as a general index of stress [20]. Histamine is released in response to stressors that could elicit or worsen migraine attacks in genetically predisposed individuals [21]. Dietary histamine, similar to other chemical food triggers, might play a role in some individuals suffering from migraines. Some foods and alcoholic beverages that are high in histamine could trigger or worsen migraine attacks in these people due to histamine’s action on the CNS [22][23]. Symptoms may be worse in individuals with histamine intolerance due to impaired histamine degradation based on reduced activity of diamine oxidase, the main enzyme involved in the metabolism of ingested histamine [24][25].

2. H1 and H2 Receptors

H1 receptor (H1R) seems to be linked to the control mechanisms of the tight junctions of the BBB. In cultured brain endothelial cells, the histaminergic system increases synaptic activity by modulating glucose intake [26]. When H1R is stimulated, it modulates vascular permeability by inducing the production of nitric oxide (NO) by activating nitric oxide synthase [11]. Studies of glyceryl trinitrate (GTN) and histamine-induced headaches have indicated that NO may initiate migraine attacks [27]. The substances that have been shown to reliably cause more headaches than placebos in single-dose experiments were GTN and histamine, with NO as the common mediator [27]. Histamine 2 receptor (H2R), abundant in the basal ganglia, amygdala, and hippocampus and commonly residing close to H1R [3], also acts in hippocampal long-term potentiation, memory consolidation, and spatial navigation and regulates vascular tone and BBB permeability [3][28]. Finally, H2R plays a role in the expression of vascular protective factors in astrocytes and brain microvascular endothelial cells [29].

3. H3 and H4 Receptors

The H3 receptor (H3R) is located presynaptically (in peripheral and CNS) and inhibits neurons, leading to the auto-inhibition of the histaminergic neurons themselves [11]. Some polymorphisms associated with impaired H3R functioning have been associated with a greater risk for the development of some neurological diseases, including migraines [30][31]. These findings can be explained by the anti-nociceptive function of these receptors [32][33][34], a function possibly related to a similar action in the modulation of the release of CGRP and pain substance (SP) through the prejunctional histamine H3R located on the peripheral endings of the sensory nerves [16]. Moreover, histamine has a selective affinity for H3R and may specifically inhibit the neurogenic edema response involved in migraine pathophysiology, modulating the vascular permeability [35][36]. The H4 receptor (H4R) shows considerable homology with the H3R (35%) and is primarily found in peripheral tissues and immune cells [11]. Recently, a functional expression of H4R within neurons of the CNS in the rat lumbar dorsal root ganglia (DRG) and in the lumbar spinal cord [3][37] has been reported [38][39]. H4R modulators may play a role in pain modulation (antinociceptive effect) as well as inflammatory and immune processes, as suggested by animal studies [37][38].

4. Mast Cells and Pain Neuromodulation

Mast cells may represent another tight link between the histaminergic system and the modulation of nociception associated with migraines [3][11][40]. The proximity of mast cells to nociceptive nerve endings in many cutaneous and deep tissues, including meninges, suggests a functional neuroimmune interaction involving mast cells and nociceptive neurons [41][42]. Migraine is generally accepted to be mediated by the prolonged activation of meningeal nociceptors [40][43]. In rat studies on meningeal nociceptors, the degranulation of dural mast cells induced a prolonged state of excitation in meningeal nociceptors. Nociceptor interaction was associated with an increased expression of nociception-associated kinases (pERK) and with a downstream activation of the nucleus of the spinal trigeminal, indicated by the increased expression of c-fos [43]. In addition, activated macrophages, microglia, and mast cells in the CNS release pro-inflammatory cytokines, which cause an increase in the arachidonic acid levels, leading to migraines and other neurological manifestations, including fatigue, nausea, and brain fog [44]. Once again, CGRP seems to be one of the molecules most involved, both through vasodilation of the dural blood vessels and through an induced degranulation of the mast cells, resulting in the extravasation of plasma proteins underlying the neurogenic inflammation and pain of migraines [40][45].


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