Next Article in Journal
Neural Correlates of Impaired Grasp Function in Children with Unilateral Spastic Cerebral Palsy
Previous Article in Journal
The Effect of Uni-Hemispheric Dual-Site Anodal tDCS on Brain Metabolic Changes in Stroke Patients: A Randomized Clinical Trial
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Brain Sciences
Volume 13
Issue 7
10.3390/brainsci13071101
brainsci-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Histamine and Its Receptors in the Mammalian Inner Ear: A Scoping Review

by
Lingyi Kong
1,
Ewa Domarecka
1 and
Agnieszka J. Szczepek
1,2,*
1
Department of Otorhinolaryngology, Head and Neck Surgery, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, 10117 Berlin, Germany
2
Faculty of Medicine and Health Sciences, University of Zielona Gora, 65-046 Zielona Gora, Poland
*
Author to whom correspondence should be addressed.
Brain Sci. 2023, 13(7), 1101; https://doi.org/10.3390/brainsci13071101
Submission received: 28 June 2023 / Revised: 14 July 2023 / Accepted: 19 July 2023 / Published: 20 July 2023
(This article belongs to the Section Neuro-otology and Neuro-ophthalmology)
Browse Figures
Review Reports Versions Notes

Abstract

:
Background: Histamine is a widely distributed biogenic amine with multiple biological functions mediated by specific receptors that determine the local effects of histamine. This review aims to summarize the published findings on the expression and functional roles of histamine receptors in the inner ear and to identify potential research hotspots and gaps. Methods: A search of the electronic databases PubMed, Web of Science, and OVID EMBASE was performed using the keywords histamine, cochlea*, and inner ear. Of the 181 studies identified, 18 eligible publications were included in the full-text analysis. Results: All four types of histamine receptors were identified in the mammalian inner ear. The functional studies of histamine in the inner ear were mainly in vitro. Clinical evidence suggests that histamine and its receptors may play a role in Ménière’s disease, but the exact mechanism is not fully understood. The effects of histamine on hearing development remain unclear. Conclusions: Existing studies have successfully determined the expression of all four histamine receptors in the mammalian inner ear. However, further functional studies are needed to explore the potential of histamine receptors as targets for the treatment of hearing and balance disorders.

1. Introduction

Histamine is a bioactive amine acting as an effector molecule of the immune system and a neurotransmitter in the nervous system. Histamine is synthesized from histidine by specific decarboxylase [1,2]. The histidine decarboxylase-expressing cells include mast cells, basophils, histaminergic neurons, and enterochromaffin-like cells in the stomach [3]. Histamine can either be secreted immediately or stored in granules for later use, as is the case with mast cells and basophils [4,5,6], which release histamine upon stimulation [7,8]. The effects of histamine range from the involvement in innate immunity [9] and its pathologies, such as allergic rhinitis [10], to housekeeping brain and bone homeostasis [4] and depend on the target cell type and the kind of histamine receptor expressed [11].
To date, four histamine receptors have been identified: the H1 receptor (H1R), H2 receptor (H2R), H3 receptor (H3R), and H4 receptor (H4R) [12,13]. All four belong to the G-protein-coupled receptor family. H1R is expressed in many tissues and cells, including cerebral neurons, the respiratory epithelium, the adrenal medulla, and hepatic, cardiovascular, and endothelial cells [1,14,15]. It is involved in allergic and inflammatory responses. When stimulated, it activates phospholipase C and increases intracellular Ca2+ levels [16,17]. As a result, the smooth muscles of the respiratory tract contract, and vascular permeability increases, subsequently causing a range of symptoms associated with allergic reactions [18]. H2R is also widely distributed and highly expressed in gastric parietal cells, vascular smooth muscles, the central nervous system, and the heart [15,19,20,21]. H3R is mainly found in the central nervous system but it is also widely distributed in peripheral tissues [22]. The effects of H3R activation are diverse and include the regulation of histamine turnover, sleep–awake regulation, learning, memory, and inflammation, as well as the inhibition of the release of several other neurotransmitters, such as serotonin, GABA, and glutamate [4,22,23]. The H4R was first described at the beginning of the 21st century [24,25,26]. The gene encoding H4R was discovered via genomic homology searches and reverse pharmacology, identifying its role in immune and pruritic responses [27]. This receptor has a relatively high homology with H3R; however, its role has yet to be elucidated [27,28].
The mammalian inner ear is a complex sensory organ consisting of the cochlea, vestibule, and three semicircular canals [29]. Sound passes from the external ear canal through the middle ear to the inner ear. In the inner ear’s cochlea, sound’s mechanical energy is converted into a biochemical signal by the sensory epithelium (hair cells) in a process called mechanotransduction. Mechanotransduction induces the release of glutamate from the inner hair cells, which activates the spiral ganglion neurons by initiating an action potential that is sequentially transmitted along the auditory pathway to the auditory cortex [30,31].
The vestibular system is responsible for sensing and processing information about the position and movement of the head and body in space and maintaining balance and coordination during the movement [32]. The peripheral vestibular organs are located bilaterally in the inner ear. They consist of two otolithic organs (utricle and saccule) and three semicircular canals (anterior, posterior, and horizontal), the former sensing linear acceleration, such as head movement or gravity, and the latter sensing rotational acceleration [33]. The sensory nerve epithelium in the utricle and saccule is the macula, and in the semicircular canals, it is the crista ampullaris [32]. Both structures contain vestibular hair cells, which release glutamate upon depolarization, stimulating the vestibular ganglion’s afferent nerves. The vestibular ganglion and the cochlear spiral ganglion neurons form the eighth cranial nerve.
The endolymphatic sac is the non-sensory part of the membranous labyrinth of the inner ear. It plays several important roles, including regulating the volume and pressure of the potassium-rich endolymph fluid, participating in the immune response within the inner ear, and removing waste products from the endolymph.
In recent years, the immune function, inflammatory processes, and vascular control of the inner ear have been investigated and reviewed [34,35,36,37]. However, the specific topic of histamine and its signaling in the cochlea or vestibular organs remains scarcely addressed in the literature. A few research teams have identified the expression of histamine receptors in the inner ear of mammals [38,39,40,41]. Additionally, in 2020, our group found mast cells in the inner ear of both rats and mice [42]. Mast cells are the major source of histamine in the body, along with basophils, gastric parietal cells, and the central nervous system [43]. Upon activation, mast cells degranulate and release a number of immuno- and neuromodulatory compounds, including histamine [44,45]. Some conditions necessary for mast cell activation have already been described regarding the inner ear, including IgE antibody transcytosis across the blood–labyrinth barrier [46] and the presence of substance P [47]. However, more research is needed to understand the relationship between the presence of mast cells in the inner ear, their mode of activation, potential histamine release, and its consequences in health and disease, such as mastocytosis or IgE-mediated diseases. Clinical evidence suggests an association between elevated numbers of mast cells and inner ear disorders [48,49]. Moreover, experiments demonstrated that Meniere’s disease-like symptoms (attacks of nystagmus and hearing loss) can be induced by the experimental induction of a type I allergy in the endolymphatic sac of guinea pigs [50].
Therefore, the purpose of this review is to provide an overview of current research investigating the expression and function of histamine and its receptors in the mammalian inner ear. A further aim is to assess the potential of the identified research for developmental, neuroprotective, and clinical applications in the inner ear. By reviewing the literature, we aim to systematically map the research that has been conducted in this area and chart the course for future research.

2. Materials and Methods

2.1. Search Strategy and Databases

This scoping review followed the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) statement [51]. A systematic search was conducted by a reviewer using the following databases: PubMed, Web of Science, and OVID EMBASE. The search window covered the period between January 2000 and June 2023. Redefined search strategies and selection criteria were used to evaluate the eligibility of studies. The keywords included the following combination of MeSH terms: histamine AND ((inner ear) OR (cochlea*)). We identified 181 publications through the database search and reference lists. The references were exported to Rayyan, a citation management system (https://rayyan.ai/, accessed on 1 June 2023). After removing duplicates, 87 articles remained in the database.

2.2. Screening Process and Inclusion and Exclusion Criteria

Two independent reviewers screened titles and abstracts of the remaining 87 articles. Criteria for the inclusion of studies in this review were English publications and studies on histamine (receptors) relevant to the mammalian inner ear or cochlea. Exclusion criteria were review articles, case reports on other topics, the lack of an English version, and non-mammalian studies. Articles not meeting the inclusion criteria and deemed irrelevant to the study were excluded.

2.3. Study Eligibility and Data Extraction

Twenty-eight publications were included for full-text eligibility assessment. After excluding publications for which the full text could not be found and research publications with non-primary research content, 18 publications were finally included in the discussion of this review. Data were extracted from each included publication to collate study characteristics and details. The PRISMA flowchart for this study is presented in Figure 1.

3. Results

3.1. Characteristics of Included Studies

A thorough evaluation of studies published between 2000 and 2023 was performed. We classified eligible publications as histamine receptor expression or functional studies in the mammalian inner ear. Nine publications investigated the expression of histamine receptors in the inner ear. The sites of expression, receptor subtypes, and species studied in the articles varied and are summarized in Table 1.
Eleven publications dealt with the functional investigation of histamine receptors. The purpose of the studies varied, including pathophysiology, pharmacological treatment, or predictive purposes, as shown in Table 2. Some studies used histamine receptor agonists or antagonists as useful tools for indirect studies of histamine function. Of the eighteen articles included in our review, eight (44.4%) used agonists or antagonists, and six of these eight studies (75%) used the H3R antagonist betahistine. We further summarized the evidence from the studies and discussed the functional context of the findings.
The main areas covered by the included studies were the anatomical/cellular localization of histamine receptors, vascular permeability, and electrophysiology. However, only one of the studies covered more than one area, combining the anatomical and electrophysiological approaches (Figure 2). One publication, which was not included in the Venn diagram [52], dealt with cochlear metabolomics.
Brainsci 13 01101 g002 550
Figure 2. Venn diagram of the main areas of coverage of the studies included in this review [38,39,40,41,53,54,55,56,57,58,59,60,61,62,63,64,65]. Red font indicates the only publication covering two areas. All publications are listed and referenced in Table 2. The study of Wang et al. was omitted in this figure as it was the only study representing metabolomics [52]. Created with BioRender.com.
Figure 2. Venn diagram of the main areas of coverage of the studies included in this review [38,39,40,41,53,54,55,56,57,58,59,60,61,62,63,64,65]. Red font indicates the only publication covering two areas. All publications are listed and referenced in Table 2. The study of Wang et al. was omitted in this figure as it was the only study representing metabolomics [52]. Created with BioRender.com.
Brainsci 13 01101 g002
Table
Table 2. Characteristics of included studies.
Table 2. Characteristics of included studies.
Author and YearLocation of StudySpeciesAge or WeightPurpose of the StudyInvolved Histamine ReceptorsInvolved Agonists or AntagonistsInner Ear Structures Focused onMain Finding(s)
Laurikainen et al. (2000) [58]FinlandGuinea pig-Function-related1 3 Yes (betahistine)CochleaThe effect of intravenous betahistine on cochlear blood flow was found to be dose-dependent and greater in the cochlear vasculature than in the systemic vascular bed, as measured with laser Doppler.
Minoda et al. (2001) [59]JapanGuinea pig (Dunkin–Hartley)300–400 gFunction-related12 Yes (pyrilamine and Cimetidine)CochleaIn low concentrations, histamine may act as an extracellular signal on inner hair cells or it may stimulate the afferent nerve by binding to their H1R and H2R.
Azuma et al. (2003) [38]JapanRat (Wistar)200–280 gExpression-related123 NoCochlea (modiolus)H1, H2, and H3R mRNA were detected in the rat cochlear modiolus.
Azuma et al. (2004) [39]JapanRat (Wistar)200–280 gExpression-related123 NoCochlea (spiral ganglion)H1R, H2R, and H3R staining was observed in spiral ganglion cells in rat cochlea. Neurofilament-200 staining indicated that HR expression is specific to type I ganglion cells.
Botta et al. (2008) [40]ItalyMouse (C57BL/6)3 weeksExpression-related1 3 NoVestibule (semicircular canal)Mouse vestibular epithelia express H1R. Conversely, no clear evidence for H3R expression was found.
Dagli et al. (2008) [41]TurkeyRabbit (New Zealand)2–3 kgExpression-related123 NoEndolymphatic sacThe endolymphatic sac of rabbits was positive for H1R, H2R and H3R. Cells positive for all receptors were found in the epithelial and subepithelial layers of the duct and the proximal endolymphatic sac.
Tritto et al. (2009) [53]ItalyMouse (Swiss CD-1)3 weeksExpression-related 3 NoVestibule (vestibular ganglion)Calyx and dimorphic neurons of mouse Scarpa’s ganglion express H3R.
Koo et al. (2011) [60]USAMouse (C57BL/6)4–7 weeksFunction-related NoCochlea (the organ of Corti)Systemic increases in serum levels of vasoactive peptides, like histamine, can modulate cochlear uptake of gentamicin, likely via permeability changes in the blood–labyrinth barriers.
Desmadryl et al. (2012) [54]FranceRat (Wistar or Long–Evans)2–8 daysExpression- and function-related 34Yes (JNJ 10191584; JNJ 7777120; 4-methylhistamine; thioperamide; betahistine)Vestibule (vestibular ganglion)H4 and H3R transcripts are present in the rat vestibular ganglion, and H4R antagonists have a significant inhibitory effect on vestibular neuron activity.
Ihler et al. (2012) [61]GermanyGuinea pig (Dunkin–Hartley)250–400 gFunction-related1 3 Yes (betahistine)Cochlea (stria vascularis)The improved effects of higher doses of betahistine in the treatment of Meniere’s disease might be due to a corresponding increase in cochlear blood flow.
Bertlich et al. (2014) [62]GermanyGuinea pig (Dunkin–Hartley)2–8 weeksFunction-related1 3 Yes (betahistine)CochleaAminoethylpyridine and hydroxyethylpyridine are, like betahistine, able to increase cochlear blood flow significantly. The effect of aminoethylpyridine was greatest. Pyridylacetic acid had no effect on cochlear microcirculation.
Egami et al. (2014) [63]JapanGuinea pig (Dunkin–Hartley)250–300 gFunction-related1 Yes (olopatadine hydrochloride)Vestibule (endolymphatic sac)The systemic sensitization with DNP-As produced allergy-induced experimental endolymphatic hydrops with type 1 hypersensitivity allergic reaction, and the development of these endolymphatic hydrops was prevented by H1R antagonists.
Bertlich et al. (2015) [64]GermanyGuinea pig (Dunkin–Hartley)180–300 gFunction-related1 3 Yes (betahistine)CochleaBetahistine affects cochlear blood flow through histaminergic H3 heteroreceptors.
Takumida et al. (2016) [56]JapanMouse (CBA/J)10 weeksExpression-related1234NoCochlea and vestibule (the organ of Corti, spiral ganglion, vestibular ganglion, endolymphatic sac, macula)All four types of histamine receptors are present in the inner ear.
Møller et al. (2016) [55]DenmarkHuman-Expression-related1234NoVestibule (endolymphatic sac)The H1R was expressed in the epithelial lining of the endolymphatic sac, whereas H3R was expressed exclusively in the subepithelial capillary network. H2R and H4R were not expressed.
Bertlich et al. (2017) [65]GermanyGuinea pig (Dunkin–Hartley)200–450 gFunction-related1 3 Yes (betahistine)Cochlea (stria vascularis)Betahistine has an active effect on cochlear microcirculation, and its main mode of action is evidently active dilation of precapillary arterioles.
Eberhard et al. (2022) [57]DenmarkHuman48–69 yearsExpression-related1 3 NoVestibule (saccule)Intense expression of the H3R was found in the non-sensory epithelial lining cells of the human saccule, whereas there was no H1R expression.
Wang et al. (2022) [52]ChinaMouse (C57BL/6)4 and 48 weeksFunction-related NoCochleaThis study represents the first comprehensive comparison of cochlear metabolites between young and old mice, revealing significant upregulation of histamine as a notable metabolic change in the cochlea of the old C57BL/6 group.

3.2. Expression of Histamine Receptors in the Mammalian Cochlea

Results from several studies have shown that histamine receptors were detected at multiple sites in the mammalian inner ear (Table 1, Figure 3) [38,39,56]. The mRNA encoding histamine receptors (H1, H2, and H3R) was found to be present in the lateral portion of the cochlea, including the spiral ligament and the stria vascularis, the medial portion, including the organ of Corti, and the modiolus [38]. Takumida et al. used immunohistochemistry (IHC) to examine the mouse cochlea and found that the stria vascularis was positive for H1R, the spiral ligament for H3R and H4R, and the spiral ganglion neurons for all four types of receptors. In the latter, immunofluorescence (IF) receptor signals were observed in the cytoplasm of the spiral ganglion neurons [56]. In the organ of Corti, H3R was observed in both the outer and inner hair cells, whereas H1R, H2R, H3R, and H4R were observed in some supporting cells [56].

3.3. Expression of Histamine Receptors in the Mammalian Vestibular System

3.3.1. Semicircular Canals

Using reverse RT-PCR, Western blotting, and in situ immunolabeling, Botta et al. demonstrated that the semicircular canal of the mouse expresses H1R [40]. Conversely, no clear evidence for H3R expression was found.

3.3.2. Utricle and Saccule

All four types of histamine receptors have been demonstrated in the maculae of the saccule and utricle [53,56]. More specifically, the expression of histamine receptors was found in type I hair cells, the calyx and dimorphic vestibular afferents, and subepithelial cells [53].

3.3.3. Vestibular Ganglion

Like in spiral ganglion neurons, H1R, H2R, H3R, and H4R were detected on vestibular ganglion cells using immunohistochemistry [53,54,56]. Tritto et al. examined vestibular neurons with immunofluorescence and found that approximately 30% of the nerves stained positively for H3R [53].

3.3.4. Endolymphatic Sac

In the murine endolymphatic sac, H1R, H2R, H3R, and H4R were detected on the epithelial cells [56]. H1R, H2R, and H3R were also found in the epithelial and subepithelial layers of the ducts and proximal endolymphatic sac of rabbits [41]. It has been shown that H3R is highly expressed in non-sensory epithelium [57], suggesting that it may play a role in maintaining cochlear fluid homeostasis. Histamine receptor expression was also found in the human endolymphatic sac. cDNA microarray data and immunohistochemical staining revealed there the presence of H1R and H3R proteins and transcripts [55]. Additionally, H1R was found in the endolymphatic sac lining, whereas H3R was present in the subepithelial capillary network [55].

4. Discussion

This scoping review evaluated the current literature concerning the expression and function of histamine and its receptors in the mammalian inner ear. All four types of histamine receptors have been found to be expressed in multiple sites of the inner ear, where they act in coordination to maintain auditory processing and balance. Therefore, it is tempting to speculate that histamine receptors might have an impact on the maintenance of inner ear function. The functional role of histamine and its receptors in the inner ear in the context of the included publications is discussed below.

4.1. Histamine Alters Vascular Permeability

One of the major physiological functions of histamine found in the inner ear is the ability to alter vascular permeability, primarily depending on H1R located on endothelial cells of the inner ear vascular lining [60,66]. A study found that histamine disrupts endothelial barrier formation in microvenules, as evidenced by changes in the localization of vascular endothelial cadherin (VE-cadherin) at endothelial cell junctions, and these manifestations can be eliminated by using H1R antagonists [66]. An increase in vascular permeability can produce beneficial physiological effects. For example, when tissue is injured or infected, an increase in vascular permeability allows white blood cells and antibodies to move out of the bloodstream and into the affected area, where they can help fight off the infection and promote healing [67]. On the other hand, an increase in vascular permeability can also help deliver nutrients and oxygen to damaged tissues, which is essential for repair and regeneration [68]. However, an excessive release of histamine can also lead to pathological effects. Koo et al. showed that vasoactive peptides, such as histamine, can enhance the ototoxicity of aminoglycosides by altering the permeability of the blood–labyrinth barrier in the mouse cochlea [60]. Like the blood–brain barrier, the blood–labyrinth barrier is composed of specialized cells and tight junctions that prevent the entry of large molecules, immune cells, and other potentially harmful substances into the inner ear from the bloodstream. These observations suggest an increased risk of ototoxicity during bacterial infections during aminoglycoside therapy, with adverse consequences for hearing function during recovery. A further exploration of this issue can reveal how to circumvent side effects and mitigate unnecessary hearing damage.

4.2. Electrophysiological Studies—The Role of Histamine in the Transmission of Electrical Signals of Sound

Only two studies have studied the electrophysiological function of histamine in the mammalian inner ear [54,59]. Previous results obtained using the vestibular organ of frogs and lateral line of Xenopus laevis have suggested that histamine may act as a hair cell transmitter [69,70,71]. These studies provided evidence that histamine increases the afferent firing rate in nerves and that this afferent firing could be blocked by H1R and H2R antagonists. Regarding guinea pigs, Minoda et al. reported that the infusion of histamine at low concentrations (10 and 50 μM) increased the compound action potential (CAP) amplitude without affecting the cochlear microphonic (CM), and the increase in CAP amplitude could be suppressed by H1R and H2R antagonists (50 μM) [59]. CAP represents the synchronous discharge of many cochlear afferent nerve fibers and is an indirect indicator of afferent nerve fiber activity. This result confirms previous findings in non-mammals. Therefore, histamine may act as an extracellular stimulatory signal that influences sound signaling via H1R and H2R in the cochlea.
Chávez et al. examined the effect of H3R agonists and antagonists on afferent neuron electrical discharge in the isolated inner ear of the axolotl [72]. They found that H3R antagonists inhibit the nerve afferent discharge in the semicircular canals. It can be hypothesized that the antivertigo action of histamine-related drugs may be caused, at least in part, by a decrease in the sensory input from the vestibular end organs. However, there are varying opinions on this matter. Earlier work regarding the semicircular canals of a frog showed that betahistine significantly reduced the resting, but not the afferent, discharge [71,73]. Unfortunately, this has not been confirmed in the mammalian vestibule. There are relatively few electrophysiological studies on H4R. Desmadry et al. found that the antagonism of H4R leads to a strong reversible inhibition of evoked action potential firing [54]. Moreover, the systemic in vivo administration of 4-methylhistamine, an H4R antagonist, effectively reduces the vestibular behavioral deficits induced by peripheral injury [54]. This demonstrates the potential role of the H4R as a pharmacological target for the treatment of vestibular disease.

4.3. Histamine May Affect Hair Cell Synaptic Transmission by Binding to Histamine 3 Receptor

H3R was originally described as an autoreceptor, inhibiting the release of histamine from histaminergic neurons in the brain [4]. H3R was shown to modulate inflammatory processes in the brain and the properties of neuronal synapses and has also been associated with the emergence of neurodevelopmental disorders [4]. Recent evidence suggests that the H3R is a pre- and postsynaptic receptor, regulating the release of several important neurotransmitters (such as acetylcholine, dopamine, GABA, norepinephrine, and serotonin) both in the peripheral and central nervous systems [4,22]. In the mammalian inner ear, the H3R has already been detected in many locations along the vestibulocochlear pathway, including the spiral ganglion and vestibular ganglion, the stria vascularis, and the endolymphatic sac [38,39,41,56]. However, it is worth mentioning that in the organ of Corti of the adult mouse, hair cells and supporting cells were also found to express H3R [56]. Glutamate is the main neurotransmitter at the hair cell afferent synapse [74]. Studies have found that histamine causes glutamate release from cultured astrocytes [4]. In addition, other studies have demonstrated that Ciproxifan, an H3R antagonist, presynaptically inhibits glutamate release in the rat hippocampus [75]. Although previous studies have confirmed the presence of H3R in the inner ear, its specific role in the regulation of afferent signaling pathways remains to be elucidated.

4.4. Clinical Application

The endolymphatic sac is a non-sensory segment of the inner ear and a part of the membranous labyrinth [76]. Its main function is to maintain the fragile endostasis of the endolymphatic and ectolymphatic vessels and to remove endolymphatic waste products [76,77]. One of the most common pathologies of the endolymphatic compartment (cochlear duct, also known as scala media) is endolymphatic hydrops. In this condition, characteristic for Menière’s disease, the excessive pressure in the cochlear duct ruptures physical barriers of the endolymphatic space causing a temporary loss of hearing and vestibular function [65,78]. The proposed causes of endolymphatic hydrops appear to be heterogeneous. Interestingly, experiments in the guinea pig have shown that histamine, released from the mast cells of the endolymphatic sac, induces a calcium response in the vestibular hair cells that is mediated by H1R, H2R, and H3R [41,79]. The histamine-mediated vasodilation of the endolymphatic sac could also lead to the deposition of immune complexes and endolymphatic effusion. These histamine-induced functional changes may be involved in the pathophysiology of Ménière’s disease.
Betahistine, a structural analog of histamine, is a weak H1R agonist and a strong H3R antagonist [64,80]. It is used to treat Ménière’s disease, particularly in central Europe [78]. Clinical trials found that repetitive daily doses of betahistine reduce the number and severity of attacks during the course of the disease [61,64]. Bertlich et al. studied the effects of betahistine on cochlear pericapillary cells and precapillary arteries and showed that the main mode of action was apparently the active dilation of the precapillary arteries [64]. Some researchers have suggested that the dilation may be due to the activation of H1R and H2R on the cochlear vasculature. The H1R and H2R expressed in the vascular smooth muscles contribute to vascular contraction and dilation [81]. A subsequent study examined changes in cochlear blood flow and blood pressure by separately blocking specific histamine receptors and found that the activation of H3R caused the decrease in cochlear blood flow and blood pressure, rather than H1R or H2R [64]. The infusion of the histaminergic H3R antagonist thioperamide prior to betahistine infusion completely reversed the effects of betahistine on cochlear blood flow [58].
Two main mechanisms of action of betahistine have been proposed. One is the counter-antagonistic effect of betahistine on H3R, which is thought to contribute to central neural compensation in the presence of peripheral vestibular imbalance [64]. The second involves an enhanced cochlear microcirculation in the stria vascularis [61,62,64]. However, betahistine may also cause clinical adverse effects, including flushing, headache, skin reactions, and hypotension, which are typical of H1R-related reactions and challenge the selectivity of the drug. The current findings provide a vision for future studies to optimize drug efficacy, for example, by targeting a specific symptom of Ménière’s disease by reducing drug side effects while maintaining efficacy.

4.5. Limitations

In the brain, researchers have found that histamine could be a disruptor of neurodevelopment [4,82]. Histamine is detected early in brain development and may therefore contribute to brain formation by regulating processes such as neuronal outgrowth, synaptogenesis, neuronal differentiation, and migration [83,84]. However, high levels of histamine can adversely affect neurodevelopment [83,84]. Suppressing neurogenesis in early development can lead to cognitive deficits and various developmental disorders.
The experimental specimens in the studies reviewed in this review were primarily from adult mammals. The expression of histamine receptors in different regions of the adult mammalian inner ear was confirmed. A quasi-targeted metabolomic analysis also indicates that the elevation of histamine in the inner ear is one of the targeted metabolic changes in age-related hearing loss [52]. However, the expression pattern of histamine receptors in the developing cochlea and the physiological role of these receptors remain unknown, and we did not identify any studies on this topic. Significant histamine receptor expression in the spiral and vestibular ganglia has been demonstrated in the available studies. However, it is still unclear when these receptors are first expressed and whether they impact the maturation of hearing and the maintenance of homeostatic function. This knowledge gap opens a field for further research.

4.6. Future Directions

The first imposing direction for future research on histamine and the inner ear is one that takes into account experiments on cochlear mast cell degranulation and its effects on inner ear morphology and physiology. In fact, some of these experiments are already underway in our laboratory and promise to provide some answers to the question of the effect of mast cell degranulation on cochlear tissue.
Furthermore, while processing the data for this review, we noticed a lack of research on the role of histamine and its receptors in inner ear development. Therefore, one of the goals of future research could be to investigate the dependence of inner ear development on the histaminergic system.
Another avenue of research could be to study the function of histamine in inner ear hair cells. Of particular interest would be the H3R, which has been found to be expressed by both outer and inner hair cells in the mouse cochlea [56], suggesting that histamine could potentially affect their function.
Finally, a thorough confirmation of histamine receptor expression in the human inner ear is needed to justify further translational research. This may be possible through initiatives such as the National Temporal Bone Registry established by the Massachusetts Eye and Ear, a teaching hospital of Harvard Medical School in Boston. In addition, pharmacologic safety monitoring of histamine receptor agonists and antagonists requires special attention to the peripheral auditory and vestibular systems.

5. Conclusions

This scoping review provides an overview of the current knowledge of histamine and its receptors in the mammalian inner ear. It highlights the evidence and potential functional significance of the presence of histamine and its receptors in hearing and balance. We have also noted that histamine-receptor-related agonists and antagonists are readily used to study histamine receptors and contribute to the treatment of Ménière’s disease. Many histamine-related drugs have been used clinically to treat otologic disorders, but research into specific mechanisms has not yet provided clear answers. This finding underscores the importance of further research into the complex molecular mechanisms of histamine and its receptors involved in auditory and vestibular function. Further research is also needed to fully understand the role of histamine receptors in inner ear development.

Author Contributions

Conceptualization, L.K. and A.J.S.; methodology, L.K. and A.J.S.; formal analysis, L.K.; investigation, L.K.; resources, L.K. and A.J.S.; data curation, L.K. and A.J.S.; writing—original draft preparation, L.K.; writing—review and editing, L.K., E.D. and A.J.S.; visualization, L.K., E.D. and A.J.S.; supervision, A.J.S.; project administration, A.J.S.; funding acquisition, A.J.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

We thank all members of our ENT research laboratory for their support.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Parsons, M.E.; Ganellin, C.R. Histamine and its receptors. Br. J. Pharmacol. 2006, 147 (Suppl. S1), S127–S135. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Lieberman, P. The basics of histamine biology. Ann. Allergy Asthma Immunol. 2011, 106, S2–S5. [Google Scholar] [CrossRef] [PubMed]
  3. Huang, H.; Li, Y.; Liang, J.; Finkelman, F.D. Molecular Regulation of Histamine Synthesis. Front. Immunol. 2018, 9, 1392. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Haas, H.L.; Sergeeva, O.A.; Selbach, O. Histamine in the nervous system. Physiol. Rev. 2008, 88, 1183–1241. [Google Scholar] [CrossRef] [PubMed]
  5. O’Mahony, L.; Akdis, M.; Akdis, C.A. Regulation of the immune response and inflammation by histamine and histamine receptors. J. Allergy Clin. Immunol. 2011, 128, 1153–1162. [Google Scholar] [CrossRef]
  6. Tanaka, S.; Furuta, K. Roles of IgE and Histamine in Mast Cell Maturation. Cells 2021, 10, 2170. [Google Scholar] [CrossRef]
  7. Uvnäs, B. The molecular basis for the storage and release of histamine in rat mast cell granules. Life Sci. 1974, 14, 2355–2366. [Google Scholar] [CrossRef]
  8. Thangam, E.B.; Jemima, E.A.; Singh, H.; Baig, M.S.; Khan, M.; Mathias, C.B.; Church, M.K.; Saluja, R. The Role of Histamine and Histamine Receptors in Mast Cell-Mediated Allergy and Inflammation: The Hunt for New Therapeutic Targets. Front. Immunol. 2018, 9, 1873. [Google Scholar] [CrossRef] [Green Version]
  9. Ferstl, R.; Akdis, C.A.; O’Mahony, L. Histamine regulation of innate and adaptive immunity. FBL 2012, 17, 40–53. [Google Scholar] [CrossRef] [Green Version]
  10. Melvin, T.A.; Ramanathan, M., Jr. Role of innate immunity in the pathogenesis of allergic rhinitis. Curr. Opin. Otolaryngol. Head Neck Surg. 2012, 20, 194–198. [Google Scholar] [CrossRef]
  11. Panula, P. Histamine receptors, agonists, and antagonists in health and disease. Handb. Clin. Neurol. 2021, 180, 377–387. [Google Scholar] [CrossRef]
  12. Cataldi, M.; Borriello, F.; Granata, F.; Annunziato, L.; Marone, G. Histamine receptors and antihistamines: From discovery to clinical applications. Chem. Immunol. Allergy 2014, 100, 214–226. [Google Scholar] [CrossRef] [Green Version]
  13. Sadek, B.; Stark, H. Cherry-picked ligands at histamine receptor subtypes. Neuropharmacology 2016, 106, 56–73. [Google Scholar] [CrossRef]
  14. Hargrove, L.; Graf-Eaton, A.; Kennedy, L.; Demieville, J.; Owens, J.; Hodges, K.; Ladd, B.; Francis, H. Isolation and characterization of hepatic mast cells from cholestatic rats. Lab. Investig. 2016, 96, 1198–1210. [Google Scholar] [CrossRef] [Green Version]
  15. Hattori, Y.; Hattori, K.; Matsuda, N. Regulation of the Cardiovascular System by Histamine. Handb. Exp. Pharmacol. 2017, 241, 239–258. [Google Scholar] [CrossRef]
  16. Wu, G.Y.; Zhuang, Q.X.; Zhang, X.Y.; Li, H.Z.; Wang, J.J.; Zhu, J.N. Facilitation of spinal α-motoneuron excitability by histamine and the underlying ionic mechanisms. Sheng Li Xue Bao 2019, 71, 809–823. [Google Scholar]
  17. Ramírez-Ponce, M.P.; Sola-García, A.; Balseiro-Gómez, S.; Maldonado, M.D.; Acosta, J.; Alés, E.; Flores, J.A. Mast Cell Changes the Phenotype of Microglia via Histamine and ATP. Cell. Physiol. Biochem. 2021, 55, 17–32. [Google Scholar] [CrossRef]
  18. MacGlashan, D., Jr. Histamine: A mediator of inflammation. J. Allergy Clin. Immunol. 2003, 112, S53–S59. [Google Scholar] [CrossRef]
  19. Orsini, J.A.; Spencer, P.A. Effects of a histamine type 2 receptor antagonist, BMY-26539-01, on equine gastric acid secretion. Can. J. Vet. Res. 2001, 65, 55–59. [Google Scholar]
  20. Wendell, S.G.; Fan, H.; Zhang, C. G Protein-Coupled Receptors in Asthma Therapy: Pharmacology and Drug Action. Pharmacol. Rev. 2020, 72, 1–49. [Google Scholar] [CrossRef] [Green Version]
  21. Neumann, J.; Kirchhefer, U.; Dhein, S.; Hofmann, B.; Gergs, U. The Roles of Cardiovascular H(2)-Histamine Receptors under Normal and Pathophysiological Conditions. Front. Pharmacol. 2021, 12, 732842. [Google Scholar] [CrossRef] [PubMed]
  22. Schlicker, E.; Kathmann, M. Role of the Histamine H(3) Receptor in the Central Nervous System. Handb. Exp. Pharmacol. 2017, 241, 277–299. [Google Scholar] [CrossRef] [PubMed]
  23. Passani, M.B.; Giannoni, P.; Bucherelli, C.; Baldi, E.; Blandina, P. Histamine in the brain: Beyond sleep and memory. Biochem. Pharmacol. 2007, 73, 1113–1122. [Google Scholar] [CrossRef]
  24. Nakamura, T.; Itadani, H.; Hidaka, Y.; Ohta, M.; Tanaka, K. Molecular cloning and characterization of a new human histamine receptor, HH4R. Biochem. Biophys. Res. Commun. 2000, 279, 615–620. [Google Scholar] [CrossRef] [PubMed]
  25. Liu, C.; Ma, X.; Jiang, X.; Wilson, S.J.; Hofstra, C.L.; Blevitt, J.; Pyati, J.; Li, X.; Chai, W.; Carruthers, N.; et al. Cloning and pharmacological characterization of a fourth histamine receptor (H(4)) expressed in bone marrow. Mol. Pharmacol. 2001, 59, 420–426. [Google Scholar] [CrossRef]
  26. Nguyen, T.; Shapiro, D.A.; George, S.R.; Setola, V.; Lee, D.K.; Cheng, R.; Rauser, L.; Lee, S.P.; Lynch, K.R.; Roth, B.L.; et al. Discovery of a novel member of the histamine receptor family. Mol. Pharmacol. 2001, 59, 427–433. [Google Scholar] [CrossRef] [Green Version]
  27. Thurmond, R.L. The histamine H4 receptor: From orphan to the clinic. Front. Pharmacol. 2015, 6, 65. [Google Scholar] [CrossRef]
  28. Connelly, W.M.; Shenton, F.C.; Lethbridge, N.; Leurs, R.; Waldvogel, H.J.; Faull, R.L.; Lees, G.; Chazot, P.L. The histamine H4 receptor is functionally expressed on neurons in the mammalian CNS. Br. J. Pharmacol. 2009, 157, 55–63. [Google Scholar] [CrossRef] [Green Version]
  29. Ekdale, E.G. Form and function of the mammalian inner ear. J. Anat. 2016, 228, 324–337. [Google Scholar] [CrossRef]
  30. Nayagam, B.A.; Muniak, M.A.; Ryugo, D.K. The spiral ganglion: Connecting the peripheral and central auditory systems. Hear. Res. 2011, 278, 2–20. [Google Scholar] [CrossRef] [Green Version]
  31. Goutman, J.D.; Elgoyhen, A.B.; Gómez-Casati, M.E. Cochlear hair cells: The sound-sensing machines. FEBS Lett. 2015, 589, 3354–3361. [Google Scholar] [CrossRef] [Green Version]
  32. Day, B.L.; Fitzpatrick, R.C. The vestibular system. Curr. Biol. 2005, 15, R583–R586. [Google Scholar] [CrossRef] [Green Version]
  33. Khan, S.; Chang, R. Anatomy of the vestibular system: A review. NeuroRehabilitation 2013, 32, 437–443. [Google Scholar] [CrossRef]
  34. Keithley, E.M. Inner ear immunity. Hear. Res. 2022, 419, 108518. [Google Scholar] [CrossRef]
  35. Ishibashi, Y.; Sung, C.Y.W.; Grati, M.; Chien, W. Immune responses in the mammalian inner ear and their implications for AAV-mediated inner ear gene therapy. Hear. Res. 2023, 432, 108735. [Google Scholar] [CrossRef]
  36. Miwa, T.; Okano, T. Role of Inner Ear Macrophages and Autoimmune/Autoinflammatory Mechanisms in the Pathophysiology of Inner Ear Disease. Front. Neurol. 2022, 13, 861992. [Google Scholar] [CrossRef]
  37. Shi, X. Pathophysiology of the cochlear intrastrial fluid-blood barrier (review). Hear. Res. 2016, 338, 52–63. [Google Scholar] [CrossRef] [Green Version]
  38. Azuma, H.; Sawada, S.; Takeuchi, S.; Higashiyama, K.; Kakigi, A.; Takeda, T. Expression of mRNA encoding the H1, H2, and H3 histamine receptors in the rat cochlea. Neuroreport 2003, 14, 423–425. [Google Scholar] [CrossRef]
  39. Azuma, H.; Sawada, S.; Takeuchi, S.; Higashiyama, K.; Kakigi, A.; Takeda, T. Immunohistochemical localization of histamine receptors in rat cochlea. Laryngoscope 2004, 114, 2249–2251. [Google Scholar] [CrossRef]
  40. Botta, L.; Tritto, S.; Perin, P.; Laforenza, U.; Gastaldi, G.; Zampini, V.; Zucca, G.; Valli, S.; Masetto, S.; Valli, P. Histamine H1 receptors are expressed in mouse and frog semicircular canal sensory epithelia. Neuroreport 2008, 19, 425–429. [Google Scholar] [CrossRef]
  41. Dagli, M.; Goksu, N.; Eryilmaz, A.; Mocan Kuzey, G.; Bayazit, Y.; Gun, B.D.; Gocer, C. Expression of histamine receptors (H(1), H(2), and H(3)) in the rabbit endolymphatic sac: An immunohistochemical study. Am. J. Otolaryngol. 2008, 29, 20–23. [Google Scholar] [CrossRef] [PubMed]
  42. Szczepek, A.J.; Dudnik, T.; Karayay, B.; Sergeeva, V.; Olze, H.; Smorodchenko, A. Mast Cells in the Auditory Periphery of Rodents. Brain Sci. 2020, 10, 697. [Google Scholar] [CrossRef] [PubMed]
  43. Scholar, E. Histamine. In xPharm: The Comprehensive Pharmacology Reference; Enna, S.J., Bylund, D.B., Eds.; Elsevier: New York, NY, USA, 2009; pp. 1–6. [Google Scholar]
  44. Church, M.K.; Kolkhir, P.; Metz, M.; Maurer, M. The role and relevance of mast cells in urticaria. Immunol. Rev. 2018, 282, 232–247. [Google Scholar] [CrossRef] [PubMed]
  45. Kolkhir, P.; Elieh-Ali-Komi, D.; Metz, M.; Siebenhaar, F.; Maurer, M. Understanding human mast cells: Lesson from therapies for allergic and non-allergic diseases. Nat. Rev. Immunol. 2022, 22, 294–308. [Google Scholar] [CrossRef] [PubMed]
  46. Zhang, N.; Lyu, Y.; Guo, J.; Liu, J.; Song, Y.; Fan, Z.; Li, X.; Li, N.; Zhang, D.; Wang, H. Bidirectional Transport of IgE by CD23 in the Inner Ear of Patients with Meniere’s Disease. J. Immunol. 2022, 208, 827–838. [Google Scholar] [CrossRef]
  47. Felix, H.; Oestreicher, E.; Felix, D.; Ehrenberger, K. Role of substance P in the peripheral vestibular and auditory system. Adv. Otorhinolaryngol. 2002, 59, 26–34. [Google Scholar]
  48. Ina, A.; Altintaş, D.U.; Yilmaz, M.; Uğuz, A.; Tuncer, U.; Kiroğlu, M.; Hergüner, O.; Bicakci, K. Congenital mastocytosis associated with neurosensory deafness. Pediatr. Dermatol. 2007, 24, 460–462. [Google Scholar] [CrossRef]
  49. Trevisan, G.; Pauluzzi, P.; Gatti, A.; Semeraro, A. Familial mastocytosis associated with neurosensory deafness. J. Eur. Acad. Dermatol. Venereol. 2000, 14, 119–122. [Google Scholar] [CrossRef]
  50. Miyamura, K.; Kanzaki, Y.; Nagata, M.; Ishikawa, T. Provocation of nystagmus and deviation by type I allergy in the inner ear of the guinea pig. Ann. Allergy 1987, 58, 36–40. [Google Scholar]
  51. Page, M.J.; Moher, D.; Bossuyt, P.M.; Boutron, I.; Hoffmann, T.C.; Mulrow, C.D.; Shamseer, L.; Tetzlaff, J.M.; Akl, E.A.; Brennan, S.E.; et al. PRISMA 2020 explanation and elaboration: Updated guidance and exemplars for reporting systematic reviews. BMJ 2021, 372, n160. [Google Scholar] [CrossRef]
  52. Wang, C.; Qiu, J.; Li, G.; Wang, J.; Liu, D.; Chen, L.; Song, X.; Cui, L.; Sun, Y. Application and prospect of quasi-targeted metabolomics in age-related hearing loss. Hear. Res. 2022, 424, 108604. [Google Scholar] [CrossRef]
  53. Tritto, S.; Botta, L.; Zampini, V.; Zucca, G.; Valli, P.; Masetto, S. Calyx and dimorphic neurons of mouse Scarpa’s ganglion express histamine H3 receptors. BMC Neurosci. 2009, 10, 70. [Google Scholar] [CrossRef] [Green Version]
  54. Desmadryl, G.; Gaboyard-Niay, S.; Brugeaud, A.; Travo, C.; Broussy, A.; Saleur, A.; Dyhrfjeld-Johnsen, J.; Wersinger, E.; Chabbert, C. Histamine H4 receptor antagonists as potent modulators of mammalian vestibular primary neuron excitability. Br. J. Pharmacol. 2012, 167, 905–916. [Google Scholar] [CrossRef] [Green Version]
  55. Møller, M.N.; Kirkeby, S.; Vikeså, J.; Nielsen, F.C.; Caye-Thomasen, P. Expression of histamine receptors in the human endolymphatic sac: The molecular rationale for betahistine use in Menieres disease. Eur. Arch. Otorhinolaryngol. 2016, 273, 1705–1710. [Google Scholar] [CrossRef]
  56. Takumida, M.; Takumida, H.; Anniko, M. Localization of histamine (H1, H2, H3 and H4) receptors in mouse inner ear. Acta Otolaryngol. 2016, 136, 537–544. [Google Scholar] [CrossRef]
  57. Eberhard, K.E.; Kirkeby, S.; Hansen, L.J.; Cayé-Thomasen, P. Neurotransmitter and neurotransmitter receptor expression in the saccule of the human vestibular system. Prog. Neurobiol. 2022, 212, 102238. [Google Scholar] [CrossRef]
  58. Laurikainen, E.; Miller, J.F.; Pyykkö, I. Betahistine effects on cochlear blood flow: From the laboratory to the clinic. Acta Otolaryngol. Suppl. 2000, 544, 5–7. [Google Scholar] [CrossRef]
  59. Minoda, R.; Toriya, T.; Masuyama, K.; Yumoto, E. The effects of histamine and its antagonists on the cochlear microphonic and the compound action potential of the guinea pig. Auris Nasus Larynx 2001, 28, 219–222. [Google Scholar] [CrossRef]
  60. Koo, J.W.; Wang, Q.; Steyger, P.S. Infection-mediated vasoactive peptides modulate cochlear uptake of fluorescent gentamicin. Audiol. Neurootol. 2011, 16, 347–358. [Google Scholar] [CrossRef] [Green Version]
  61. Ihler, F.; Bertlich, M.; Sharaf, K.; Strieth, S.; Strupp, M.; Canis, M. Betahistine exerts a dose-dependent effect on cochlear stria vascularis blood flow in guinea pigs in vivo. PLoS ONE 2012, 7, e39086. [Google Scholar] [CrossRef] [Green Version]
  62. Bertlich, M.; Ihler, F.; Sharaf, K.; Weiss, B.G.; Strupp, M.; Canis, M. Betahistine metabolites, aminoethylpyridine, and hydroxyethylpyridine increase cochlear blood flow in guinea pigs in vivo. Int. J. Audiol. 2014, 53, 753–759. [Google Scholar] [CrossRef] [PubMed]
  63. Egami, N.; Kakigi, A.; Takeda, T.; Takeda, S.; Nishioka, R.; Hyodo, M.; Yamasoba, T. Type 1 allergy-induced endolymphatic hydrops and the suppressive effect of H1-receptor antagonist (olopatadine hydrochloride). Otol. Neurotol. 2014, 35, e104–e109. [Google Scholar] [CrossRef] [PubMed]
  64. Bertlich, M.; Ihler, F.; Freytag, S.; Weiss, B.G.; Strupp, M.; Canis, M. Histaminergic H3-Heteroreceptors as a Potential Mediator of Betahistine-Induced Increase in Cochlear Blood Flow. Audiol. Neurootol. 2015, 20, 283–293. [Google Scholar] [CrossRef] [PubMed]
  65. Bertlich, M.; Ihler, F.; Weiss, B.G.; Freytag, S.; Strupp, M.; Jakob, M.; Canis, M. Role of capillary pericytes and precapillary arterioles in the vascular mechanism of betahistine in a guinea pig inner ear model. Life Sci. 2017, 187, 17–21. [Google Scholar] [CrossRef] [PubMed]
  66. Ashina, K.; Tsubosaka, Y.; Nakamura, T.; Omori, K.; Kobayashi, K.; Hori, M.; Ozaki, H.; Murata, T. Histamine Induces Vascular Hyperpermeability by Increasing Blood Flow and Endothelial Barrier Disruption In Vivo. PLoS ONE 2015, 10, e0132367. [Google Scholar] [CrossRef]
  67. Park-Windhol, C.; D’Amore, P.A. Disorders of Vascular Permeability. Annu. Rev. Pathol. 2016, 11, 251–281. [Google Scholar] [CrossRef]
  68. Dvorak, H.F. Vascular permeability to plasma, plasma proteins, and cells: An update. Curr. Opin. Hematol. 2010, 17, 225–229. [Google Scholar] [CrossRef]
  69. Housley, G.D.; Norris, C.H.; Guth, P.S. Histamine and related substances influence neurotransmission in the semicircular canal. Hear. Res. 1988, 35, 87–97. [Google Scholar] [CrossRef]
  70. Bledsoe, S.C., Jr.; Sinard, R.J.; Allen, S.J. Analysis of histamine as a hair-cell transmitter in the lateral line of Xenopus laevis. Hear. Res. 1989, 38, 81–93. [Google Scholar] [CrossRef]
  71. Botta, L.; Mira, E.; Valli, S.; Perin, P.; Zucca, G.; Valli, P. Effects of betahistine on vestibular receptors of the frog. Acta Otolaryngol. 1998, 118, 519–523. [Google Scholar] [CrossRef]
  72. Chávez, H.; Vega, R.; Soto, E. Histamine (H3) receptors modulate the excitatory amino acid receptor response of the vestibular afferents. Brain Res. 2005, 1064, 1–9. [Google Scholar] [CrossRef]
  73. Botta, L.; Mira, E.; Valli, S.; Zucca, G.; Benvenuti, C.; Fossati, A.; Soto, E.; Guth, P.; Valli, P. Effects of betahistine and of its metabolites on vestibular sensory organs. Acta Otorhinolaryngol. Ital. 2001, 21, 24–30. [Google Scholar]
  74. Glowatzki, E.; Grant, L.; Fuchs, P. Hair cell afferent synapses. Curr. Opin. Neurobiol. 2008, 18, 389–395. [Google Scholar] [CrossRef] [Green Version]
  75. Lu, C.W.; Lin, T.Y.; Chang, C.Y.; Huang, S.K.; Wang, S.J. Ciproxifan, a histamine H(3) receptor antagonist and inverse agonist, presynaptically inhibits glutamate release in rat hippocampus. Toxicol. Appl. Pharmacol. 2017, 319, 12–21. [Google Scholar] [CrossRef]
  76. Kim, S.H.; Nam, G.S.; Choi, J.Y. Pathophysiologic Findings in the Human Endolymphatic Sac in Endolymphatic Hydrops: Functional and Molecular Evidence. Ann. Otol. Rhinol. Laryngol. 2019, 128, 76s–83s. [Google Scholar] [CrossRef]
  77. Lo, W.W.; Daniels, D.L.; Chakeres, D.W.; Linthicum, F.H., Jr.; Ulmer, J.L.; Mark, L.P.; Swartz, J.D. The endolymphatic duct and sac. AJNR Am. J. Neuroradiol. 1997, 18, 881–887. [Google Scholar]
  78. Nakashima, T.; Pyykkö, I.; Arroll, M.A.; Casselbrant, M.L.; Foster, C.A.; Manzoor, N.F.; Megerian, C.A.; Naganawa, S.; Young, Y.H. Meniere’s disease. Nat. Rev. Dis. Primers 2016, 2, 16028. [Google Scholar] [CrossRef]
  79. Tomoda, K.; Nagata, M.; Harada, N.; Iwai, H.; Yamashita, T. Effect of histamine on intracellular Ca2+ concentration in guinea pig isolated vestibular hair cells. Acta Otolaryngol. Suppl. 1997, 528, 37–40. [Google Scholar]
  80. Holmes, S.; Lalwani, A.K.; Mankekar, G. Is Betahistine Effective in the Treatment of Ménière’s Disease? Laryngoscope 2021, 131, 2639–2640. [Google Scholar] [CrossRef]
  81. Miller, D.J.; O’Dowd, A. Vascular smooth muscle actions of carnosine as its zinc complex are mediated by histamine H(1) and H(2) receptors. Biochemistry 2000, 65, 798–806. [Google Scholar]
  82. Lieberman, P. Histamine, antihistamines, and the central nervous system. Allergy Asthma Proc. 2009, 30, 482–486. [Google Scholar] [CrossRef] [PubMed]
  83. Molina-Hernández, A.; Díaz, N.F.; Arias-Montaño, J.A. Histamine in brain development. J. Neurochem. 2012, 122, 872–882. [Google Scholar] [CrossRef] [PubMed]
  84. Panula, P.; Sundvik, M.; Karlstedt, K. Developmental roles of brain histamine. Trends Neurosci. 2014, 37, 159–168. [Google Scholar] [CrossRef] [PubMed]
Brainsci 13 01101 g001 550
Figure 1. PRISMA study flow diagram. “N” signifies the number of databases; “n” signifies the number of publications.
Figure 1. PRISMA study flow diagram. “N” signifies the number of databases; “n” signifies the number of publications.
Brainsci 13 01101 g001
Brainsci 13 01101 g003 550
Figure 3. Distribution of histamine receptors in the mammalian inner ear. Created with BioRender.com.
Figure 3. Distribution of histamine receptors in the mammalian inner ear. Created with BioRender.com.
Brainsci 13 01101 g003
Table
Table 1. Sites and subtypes of histamine receptor expression in the mammalian inner ear.
Table 1. Sites and subtypes of histamine receptor expression in the mammalian inner ear.
Author and YearSpeciesAge or WeightExperimental MethodsH1RLocationsH2RLocationsH3RLocationsH4RLocations
Azuma et al. (2003) [38]Rat (Wistar)200–280 gPCR✓modiolus✓modiolus✓modiolusn.d.
Azuma et al. (2004) [39]Rat (Wistar)200–280 gIHC✓spiral ganglion✓spiral ganglion✓spiral ganglionn.d.
Botta et al. (2008) [40]Mouse (C57BL/6)3 weeksPCR; IF✓semicircular canaln.d. ✓semicircular canaln.d.
Dagli et al. (2008) [41]Rabbit (New Zealand)2000–3000 gIHC✓endolymphatic sac✓endolymphatic sac✓endolymphatic sacn.d.
Tritto et al. (2009) [52]Mouse (Swiss CD-1)3 weeksPCR; IFn.d. n.d. ✓vestibular ganglionn.d.
Desmadryl et al. (2012) [53]Rat (Wistar)2–8 daysPCRn.d. n.d. ✓vestibular ganglion✓vestibular ganglion
Møller et al. (2016) [54]Humann.s.IHC, microarrays✓endolymphatic sac (IHC, microarrays)✓endolymphatic sac (microarrays, expression greater than in dura)✓endolymphatic sac (IHC, microarrays)✓endolymphatic sac (microarrays, expression lesser than in dura)
Takumida et al. (2016) [55]Mouse (CBA/J)10 weeks (25–30 g)IHC; PCR✓stria vascularis; the organ of Corti; spiral ganglion; vestibular ganglion; vestibular epithelium; endolymphatic sac✓spiral ganglion; vestibular ganglion; vestibular epithelium; endolymphatic sac✓spiral ligament; the organ of Corti; spiral ganglion; vestibular ganglion; vestibular epithelium; endolymphatic sac✓spiral ligament; the organ of Corti; spiral ganglion; vestibular ganglion; vestibular epithelium; endolymphatic sac
Eberhard et al. (2022) [56]Human48–69 yearsIHCneg.sacculen.d. ✓sacculen.d.
Abbreviations: PCR, polymerase chain reaction; IF, immunofluorescence; IHC, immunohistochemistry. “✓”—indicates the confirmed presence of a given histamine receptor; “n.d.”—not done; “n.s.” not stated; “neg.”—negative results.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Kong, L.; Domarecka, E.; Szczepek, A.J. Histamine and Its Receptors in the Mammalian Inner Ear: A Scoping Review. Brain Sci. 2023, 13, 1101. https://doi.org/10.3390/brainsci13071101

AMA Style

Kong L, Domarecka E, Szczepek AJ. Histamine and Its Receptors in the Mammalian Inner Ear: A Scoping Review. Brain Sciences. 2023; 13(7):1101. https://doi.org/10.3390/brainsci13071101

Chicago/Turabian Style

Kong, Lingyi, Ewa Domarecka, and Agnieszka J. Szczepek. 2023. "Histamine and Its Receptors in the Mammalian Inner Ear: A Scoping Review" Brain Sciences 13, no. 7: 1101. https://doi.org/10.3390/brainsci13071101

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop