The expression ofNF-κB, thetranscription factor that regulates inflammatory processes, is promoted by theconstitutive activity of the H1 receptor as well as by agonists that bind at the receptor.[7]H1-antihistamines have been shown to attenuate NF-κB expression and mitigate certain inflammatory processes in associated cells.[7]
Histamine H1 receptors are activated by endogenous histamine, which is released by neurons that have their cell bodies in thetuberomammillary nucleus of thehypothalamus. The histaminergic neurons of the tuberomammillary nucleus become active during the 'wake' cycle, firing at approximately 2 Hz; duringslow wave sleep, this firing rate drops to approximately 0.5 Hz. Finally, duringREM sleep, histaminergic neurons stop firing altogether. It has been reported that histaminergic neurons have the most wake-selective firing pattern of all known neuronal types.[9]
Thetuberomammillary nucleus is a histaminergic nucleus that strongly regulates the sleep-wake cycle.[10] H1-antihistamines that cross theblood–brain barrier inhibit H1 receptor activity on neurons that project from the tuberomammillary nucleus. This action is responsible for the drowsiness effect associated with these drugs.[citation needed]
A recent study published in August 2024 suggested that H1 receptor can act as an alternative entry point for theSARS-CoV-2 (COVID-19) virus to infect cells, in addition to the main receptorACE2. HRH1 also synergistically enhanced hACE2-dependent viral entry by interacting with hACE2. Antihistamine drugs effectively prevent viral infection by competitively binding to HRH1, thereby disrupting the interaction between the spike protein and its receptor.[11]
^abCanonica GW, Blaiss M (February 2011)."Antihistaminic, anti-inflammatory, and antiallergic properties of the nonsedating second-generation antihistamine desloratadine: a review of the evidence".The World Allergy Organization Journal.4 (2):47–53.doi:10.1097/WOX.0b013e3182093e19.PMC3500039.PMID23268457.The H1-receptor is a transmembrane protein belonging to the G-protein coupled receptor family. Signal transduction from the extracellular to the intracellular environment occurs as the GPCR becomes activated after binding of a specific ligand or agonist. A subunit of the G-protein subsequently dissociates and affects intracellular messaging including downstream signaling accomplished through various intermediaries such as cyclic AMP, cyclic GMP, calcium, and nuclear factor kappa B (NF-κB), a ubiquitous transcription factor thought to play an important role in immune-cell chemotaxis, proinflammatory cytokine production, expression of cell adhesion molecules, and other allergic and inflammatory conditions.1,8,12,30–32 ... For example, the H1-receptor promotes NF-κB in both a constitutive and agonist-dependent manner and all clinically available H1-antihistamines inhibit constitutive H1-receptor-mediated NF-κB production ... Importantly, because antihistamines can theoretically behave as inverse agonists or neutral antagonists, they are more properly described as H1-antihistamines rather than H1-receptor antagonists.15
^Cará AM, Lopes-Martins RA, Antunes E, Nahoum CR, De Nucci G (February 1995). "The role of histamine in human penile erection".British Journal of Urology.75 (2):220–224.doi:10.1111/j.1464-410x.1995.tb07315.x.PMID7850330.
^Passani MB, Lin JS, Hancock A, Crochet S, Blandina P (December 2004). "The histamine H3 receptor as a novel therapeutic target for cognitive and sleep disorders".Trends in Pharmacological Sciences.25 (12):618–625.doi:10.1016/j.tips.2004.10.003.PMID15530639.
^Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin". In Sydor A, Brown RY (eds.).Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 175–176.ISBN9780071481274.Within the brain, histamine is synthesized exclusively by neurons with their cell bodies in the tuberomammillary nucleus (TMN) that lies within the posterior hypothalamus. There are approximately 64000 histaminergic neurons per side in humans. These cells project throughout the brain and spinal cord. Areas that receive especially dense projections include the cerebral cortex, hippocampus, neostriatum, nucleus accumbens, amygdala, and hypothalamus. ... While the best characterized function of the histamine system in the brain is regulation of sleep and arousal, histamine is also involved in learning and memory ... It also appears that histamine is involved in the regulation of feeding and energy balance.
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"Histamine Receptors: H1".IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived fromthe original on 2016-03-03. Retrieved2006-07-20.
