br Introduction Histamine stored in mast cells and basophils

Introduction Histamine stored in mast cells and basophils has been recognized as one of the most critical mediators in allergic reactions and plays an important role in eliciting the nasal symptoms of allergic rhinitis, such as sneezing, nasal itch, pain, rhinorrhea, and congestion [1], [2]. It is now clear that histamine exerts its diverse biological effects by binding to and activating four separate G protein-coupled receptors, referred to as histamine H1 receptor (H1R) [3], histamine H2 receptor (H2R) [4], histamine H3 receptor (H3R) [5], and histamine H4 receptor (H4R) [6]. These four histamine receptor subtypes differ in their tissue distribution, agonist- and antagonist-binding affinities, structures, and functions. Stimulation of the H1R leads to contraction of tracheal and vascular smooth muscles, elevation of vascular permeability, and stimulation of sensory nerve endings [7]. H2R mainly mediates gastric (R)-baclofen synthesis secretion and airway and vascular smooth muscle relaxation [7]. H3R can act as an autoreceptor controlling histamine synthesis and release [7] or a heteroreceptor regulating the release of neurotransmitters, such as acetylcholine, dopamine, noradrenaline, serotonin, glutamate, substance P, and gamma-aminobutyric acid [8], [9]. H4R is expressed by immunologically relevant tissues, such as spleen, thymus, mast cells, and eosinophiles and considered to exhibit immunomodulatory functions [10], [11]. All four histamine receptor subtypes have been identified in human inferior turbinates [12], [13], [14], [15].These receptors are involved in the pathogenesis of allergic rhinitis. H1R is thought to be heavily involved with histamine-induced inflammation in the nasal mucosa. Its antagonists reduced nasal symptoms of sneezing, nasal itch, rhinorrhea, and congestion [16], [17], [18] with a decrease of the number of eosinophils in rodent models of allergic rhinitis [18]. In guinea pigs, it was reported that 20% of nasally labeled, dissociated sensory neurons responded to histamine, which was inhibited by H1R antagonist diphenhydramine [19]. Intranasal challenge with H2R agonists has been shown to cause nasal congestion, but failed to produce any other symptoms [20], [21]. These responses were abolished by H2R antagonist pretreatment. Based on the findings in other vascular systems, the H2R-mediated nasal congestion is most likely due to the activation of H2R on the vascular smooth muscle, causing endothelial-independent vasodilation [22]. The role of H3R in nasal pathophysiology was reported in an experimental model of allergic nasal congestion [23]. In this study the nasal congestion caused by a mast cell degranulator, was reduced by an intravenous administration of a combination of H1R and H3R antagonists. Neither H1R nor H3R antagonist was effective when given alone. H4R antagonist caused a significant inhibition of sneezing, nasal rubbing, and serum total IgE, with a decrease in the levels of IL-4 and an increase in the levels of INF-γ in nasal lavage [24]. Until now, investigation histamine receptors in nasal mucosa have almost completely focused on the role of inflammatory reaction in nasal respiratory mucosa. The olfactory epithelium (OE) located at the dorsal part of the nasal cavity is segregated from the respiratory mucosa and harbors the olfactory receptor neurons (ORNs) for smell. A few studies speculated that histamine may play a role in the modulation of olfactory transmission. To identify the functions of histamine in the mammalian OE, better understanding of the distribution of each histamine receptor subtype is crucial. However, to our knowledge there is no report concerning the presence of histamine receptors in OE. The aim of the present study was to determine the expression and distribution of H1R, H2R, and H3R in rat OE by real-time quantitative PCR and immunohistochemistry technique.
Materials and methods
Results
Discussion The presence and function of histamine and its receptors in nasal respiratory mucosa have been previously reported, but whether histamine receptors are present in OE remain unexplored. In this study, we showed that mRNAs encoding H1R, H2R, and H3R are expressed in rat OE by real-time quantitative PCR. Furthermore, our immunohistochemical results demonstrated that H1R, H2R, and H3R are localized in the cytoplasm of ORNs in OE.