[Frontiers in Bioscience S4, 226-239, January 1, 2012]
Role of histamine H4 receptors in the gastrointestinal tract
Gabriella Coruzzi1, Maristella Adami1, Cristina Pozzoli1
1
TABLE OF CONTENTS
1. ABSTRACT
The location and functional role of histamine H4 receptors (H4Rs) in the gastrointestinal tract (GI) is reviewed, with particular reference to their involvement in the regulation of gastric acid secretion, gastric mucosal defense, intestinal motility and secretion, visceral sensitivity, inflammation, immunity and carcinogenesis. H4Rs have been detected in different cell types of the gut, including immune cells, paracrine cells, endocrine cells and neurons; moreover, H4R expression was reported in human colorectal cancer specimens. Functional studies with selective H4R ligands demonstrated protective effects in several experimental models of gastric mucosal damage and intestinal inflammation, suggesting a potential therapeutic role of drugs targeting this new receptor subtype in GI disorders, such as allergic enteropathy, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) and cancer.
2. INTRODUCTION
Histamine is a pleiotropic biogenic amine with a broad range of activities in both physiological and pathological conditions. Both histamine producing cells and receptors are extensively distributed within the body, suggesting that this amine is an important regulator of a wide variety of functions. Despite the intestinal effects of histamine were firstly described one century ago in the landmark paper by Dale and Laidlaw (1), research mainly focused on immunological and inflammatory effects of this amine, leading to the discovery of the histamine H1 receptor (H1R) antagonists, as the first anti-allergic drugs (2). In 1972, thanks to the pioneering work of Sir James Black and coworkers, the central role of histamine in the regulation of parietal cell acid secretion was clearly defined and histamine H2 receptor (H2R) antagonists became the standard therapy of gastric acid related diseases (3-5). Since then, two further receptor subtypes have been discovered, namely H3 and H4, and the research on histamine gained considerable interest again (6-12). Therapeutic fields have emerged for H3 receptor (H3R) ligands, with selective antagonists representing new drugs for cognitive, sleep and memory disorders (13, 14) and for obesity (15); on the other hand, based on the predominant location of H4 receptors (H4Rs) in immune and inflammatory cells, selective antagonists of this receptor are currently the object of intensive research, as potential candidates in the therapy of allergy, inflammatory disorders, neurophatic pain and pruritus (16-21). A large body of evidence has unraveled the occurrence of H4Rs in the gastrointestinal (GI) tract, together with protective effects mediated by H4R ligands in experimental models of GI damage, thus suggesting that this novel receptor subtype might represent a potential drug target in the treatment of functional GI diseases.
In the present review we report the available data concerning the location and functional role of histamine H4Rs in the GI tract and the potential clinical implications for human diseases.
3. HISTAMINE IN THE GI TRACT: CELLULAR SOURCES, TARGETS AND RECEPTORS
In the GI tract, histamine is synthesized by histidine decarboxylase (HDC) enzyme and stored in various cell types, including mast cells, basophils, and enterochromaffin-like (ECL) cells; few reports suggest the occurrence of histamine in G cells and enteric neurons (Figure 1) (22-26). In addition, several myeloid and lymphoid cell types (dendritic cells, neutrophils, monocytes/macrophages, T cells and platelets), which do not store histamine, show high HDC activity and are capable of producing histamine to a varying degree, following activation by allergens, mitogens or cytokines (27-30). Finally, most malignant cells contain high concentrations of histamine that can regulate tumour growth via a paracrine or autocrine pathway (Figure 1) (31). Histamine stores greatly vary among species: in dogs and humans, mast cells account for the major histamine content; they are predominantly located in the mucosal surfaces of the whole GI tract and are mainly involved in IgE-mediated hypersensitivity in response to allergens and in reactions against parasites (32). In rodents, ECL cells are recognized as the major histamine-producing cells in the gastric mucosa, thereby representing a central regulatory pathway for the secretion of acid via the parietal cell (33, 34). Elevated concentrations of histamine have been shown in various inflammatory and neoplastic diseases, such as Crohn's disease, ulcerative colitis, irritable bowel syndrome (IBS), allergic enteropathy and colorectal cancer (32, 35-38).
In the GI tract, histamine plays a role in a number of processes, including acid secretion, mucosal defense, fluid transport, neurotransmission, inflammation, immunity and carcinogenesis, targeting a variety of cell types (Figure 1) (28, 31, 32, 39-42). These different biological functions involve the four known histamine receptor subtypes, identified to date, H1, H2, H3 and H4, which are differently expressed along the gut. Histamine H1Rs mediate vasodilatation and increase in vascular permeability, smooth muscle contraction, intestinal fluid transport and visceral sensitivity; H2Rs are mainly responsible for the physiological regulation of acid secretion from parietal cells, but also influence intestinal secretion, neurotransmission and immune responses; H3Rs are primarily involved in gastric mucosal defense, inhibition of enteric neurotransmission and feedback regulation of histamine release (32, 43-46). Preliminary functional studies in transfected cells and in vivo experimental models seem to suggest the participation of H4Rs in the GI effects of histamine. The H4R has been shown to mediate a number of proinflammatory effects, including neutrophil, mast cell and eosinophil chemotaxis and release of inflammatory cytokines, thus representing a novel target in inflammatory GI diseases (17).
4. EXPRESSION OF H4Rs IN THE GI TRACT
In the last decade, the occurrence of H4Rs in the GI tract of different species, including humans, was demonstrated by the use of several techniques, such as quantitative reverse transcription-polymerase chain reaction (qRT-PCR), Western blot analysis and immunostaining (summarized in Table 1) (7-12, 47-59). Under physiological conditions, H4R expression is rather low, as compared with bone marrow, spleen or liver, but it may be regulated by inflammatory stimuli. A recent study demonstrated a significant increase in H4R density after treatment of mice with trinitrobenzenesulphonic acid (TNBS), a widely used model of inflammation, which reproduces human Crohn's disease (56, 60). More recently, it was reported that H4R expression increases in the colon of mice genetically deficient of the Gi protein alpha2 subunit and the increase in receptor density parallel the colitis progression (61). The presence of H4Rs was demonstrated in the human normal intestine and their distribution pattern was described in detail by histological analysis (49, 51, 53); H4R staining was detected in leukocytes inside the small mucosal and submucosal vessels, neuroendocrine cells and, finally, in enterocytes at the apical end of the crypts of Lieberkun (51). The same study reported an increased expression of both H1Rs and H2Rs in patients with IBS or food allergies, with no change in H4R mRNA levels (51). By contrast, H4R expression was found to be reduced in colorectal cancer specimens, as compared to normal colonic tissue (49, 53).
5. HISTAMINE H4R SELECTIVE LIGANDS
Since the cloning of the H4R, a variety of ligands have been identified in search of selective tools to unravel H4R-mediated tissue functions and of potential drug candidates (18-20, 62). In accordance with the high homology between H4R and H3R, most of the first-generation H3R ligands (like imetit, immepip, thioperamide and clobenpropit) are now known to bind to the H4R (16). The first highly selective histamine H4R antagonist, namely JNJ7777120, was developed by Johnson and Johnson Pharmaceuticals and it became the reference antagonist for pharmacological investigation, displaying more than a thousand fold selectivity over other receptor subtypes (19, 63, 64). Other H4R antagonists were developed by academic research groups and by several pharmaceutical companies (58, 62, 65, 66). Histamine H4R agonists were also described, such as 4-methylhistamine and VUF8430; these compounds, however, still retain affinity for the other histamine receptor subtypes (67, 68). To complicate matters, the selectivity profile of most H4R ligands was found to greatly vary according to the species; in addition, some ligands were found to behave as "protean" ligands, displaying antagonism, partial, total or inverse agonism activity, depending on the experimental assay (69,70). This hampers a clear understanding of H4R pharmacology; in line with this, some studies were unable to ascribe the observed effects to agonism or antagonism at H4Rs (71, 72). To support this, a recent study in rats reported that ischemia/reperfusion liver injury was reduced by H4R stimulation and not blockade, as expected from the supposed inflammatory activity mediated by H4Rs (73).
6. EFFECTS OF H4R LIGANDS IN THE GI TRACT
Several studies have reported functional effects of H4R ligands in both in vitro assays and in intact animals. Most data were obtained in rodents by the use of the reference H4R antagonist JNJ7777120 (Tables 2 and 3).
6.1. Gastric acid secretion
The major role of histamine and of H2Rs in the stomach is the regulation of acid secretion by the parietal cell, as demonstrated in humans by the clinical efficacy of H2R antagonists in various clinical settings (4, 5). Whereas gastric H1Rs are mainly involved in the vasodilation and reactive hyperemia in response to acid challenge (39, 45, 74, 75), the role of H3Rs is unclear. H3Rs were detected in various cell types of the gastric mucosa, including ECL cells, cholinergic neurons and somatostatin D cells (39, 40, 43, 55); however, functional data were dependent on the species and the experimental assay (40, 44, 46). The negative regulation of histamine release from ECL cells has been proposed by several authors as the main function mediated by H3Rs in the rat stomach (33, 43).
Early studies have reported a low H4R expression in the human and rat stomach (Table 1); recently, more detailed information about the cell distribution of H4Rs in the rat gastric mucosa was obtained by immunohistochemistry (55). In particular, as opposed to H3Rs, H4Rs do not occur in ECL cells and seem to be selectively located in endocrine cells (A-like cells) of the fundic mucosa producing the orexigenic peptide ghrelin (55). Functional experiments obtained in our lab in the anaesthetised rats with lumen-perfused stomach showed that the selective H4R antagonist JNJ7777120 and its benzimidazole derivative VUF6002 (76) did not modify basal acid secretion or the hypersecretion induced by histamine; in addition, only JNJ7777120 reduced the acid secretion induced by pentagastrin (M. Adami, unpublished observations). The hypothesis of gastric secretory effects induced by H4R activation, was not confirmed by the use of the H4R agonist VUF8430, since the increase in acid secretion induced by this compound was fully prevented by the H2R antagonist ranitidine and not by JNJ7777120 (77). In conclusion, the relevance of histamine H4Rs in parietal cell function is still to be elucidated.
6.2. Gastric mucosal defense
As opposed to the key role played by histamine in the regulation of parietal cell function, its role in gastric mucosal defense has long been debated, since H1R or H2R selective ligands displayed either ulcerogenic or protective effects (44). The discovery of histamine H3Rs and the use of (R)-alpha-methylhistamine and thioperamide have highlighted the protective effect of histamine in the gastric mucosa, since H3R activation prevented the acute mucosal damage induced in rats by absolute ethanol, non-steroidal anti-inflammatory drugs, ammonia, concentrated HCl or stress (78-83). The protective effect was related to increase in mucus production, gastric mucosal blood flow, epithelial cell proliferation and activation of sensory nerves (83-85).
Data from our group have suggested a possible involvement of H4Rs in histamine-mediated effects on mucosal defense (86); HCl-induced gastric lesions were not reduced by immepip and imetit, two formerly described as highly selective H3R agonists, which are now known to display considerable affinity at histamine H4Rs (16, 67). Indeed, subsequent data from our lab obtained with the selective H4R antagonist JNJ7777120, would indicate that H4Rs are involved in the ulcerogenic effects of histamine (71, 87). This compound was found to protect the rat and mouse gastric mucosa from the damaging effect of non steroidal anti-inflammatory agents and the mast cell degranulator compound 48/80 (Table 3). However, preliminary experiments from our group showed that in rats, but not in mice, the selective H4R agonist VUF8430 significantly reduced indomethacin-induced lesions (Figure 2, Table 3) (71). From the available data, it is difficult to make a clear picture of the functional role of H4Rs in the rat gastric mucosa, due to the similar behaviour displayed by H4R agonists and antagonists. The occurrence of H4Rs in endocrine cells of the rat fundus producing ghrelin (55, 88) could lead to speculate a possible role of histamine in the secretion of this peptide (Figure 3). In line with this, a link between histamine and ghrelin was indicated by recent data from our group, showing that ghrelin-induced gastroprotection is prevented by both H3R and H4R antagonists (89).
6.3. Intestinal motility and secretion
The intestinal effects of histamine were among the first effects of histamine described by Dale and Laidlaw (1). Nevertheless, most attention was devoted to the functional activity of histamine in the stomach and the effects on the bowel were disregarded. In the recent years, it has become apparent that intestinal mast cell mediators and enteric nervous system are key players in the intricate neuroimmune network, that regulates intestinal homeostasis and the inflammatory response to noxious stimuli (90). Histamine can influence neurotransmission at both submucous and myenteric plexus, thereby modifying intestinal secretion and motility, through the activation of the three receptors H1, H2 and H3 (32, 39, 45, 46, 91-93). The occurrence of a new receptor subtype in the intestine was firstly hypothesized by Schworer et al (94), who identified in the porcine small intestine an H3-like receptor that was pharmacologically distinct from the proposed H3a and H3b receptors. These findings were subsequently confirmed by Oda et al (8), who characterized a new histamine receptor (called GPRv53) expressed in the small intestine, and afterwards by several independent groups (Table 1) (7-12).
Despite the presence of H4Rs in the rodent myenteric plexus (52), the role of this receptor in the regulation of intestinal motility is apparently absent. In our lab, we were unable to detect any effect of either agonists or antagonists of H4Rs on cholinergic neurotransmission in the isolated rat duodenum (95). Likewise, histamine H4R ligands did not modify spontaneous or electrically-evoked motility in surgical specimens from human colon, suggesting that this receptor subtype does not play a role in the regulation of intestinal muscle contractility in humans (Table 2).
The stimulatory effects of histamine on intestinal transport were widely demonstrated in guinea pigs and humans (32, 92, 93, 96, 97). However, the receptor involved seems to differ across species: in the guinea pig, histamine increases intestinal ion and water secretion in both small and large intestine, via activation of H2Rs located on epithelial cells and on colonic submucous plexus (96). In addition, prejunctional H3Rs negatively modulate cholinergically-mediated intestinal secretion by removing the inhibitory control exerted by the adrenergic system (96). As opposed to animal findings, in the human intestine, histamine-induced increase in chloride secretion by colonic epithelium was exclusively related to activation of H1Rs (92). A recent study in human submucous plexus from surgical specimens suggests, however, that histamine may induce excitation of enteric neurons through activation of all four histamine receptors (H1R-H4R) (98). The H3R-mediated excitatory effects on secretory neurons reported in this study are unexpected, in view of data from the literature showing lack of H3R expression in the human bowel or of H3R-mediated effects on intestinal contractility (51, 99). The pathophysiological significance of the excitatory action of histamine on secretory neurons is uncertain; hyperactivity of these neurons leads to neurogenic secretory diarrhoea, as observed in various pathological conditions, such as ulcerative colitis, Crohn's disease, allergic enteropathy or parasitic infection (90). In this connection, mast cells in colonic mucosal biopsies from IBS patients with diarrhoea release more histamine than in normal subjects (37); thus, it can be speculated that H4R antagonists may be of therapeutic value in these GI disorders, as observed for mast cell stabilizers or H2R antagonists (100, 101).
6.4. Visceral sensitivity
Visceral hypersensitivity is widely accepted as a mechanism that can explain many clinical symptoms associated with organic and functional bowel diseases (90, 102). Histamine, as other inflammatory mediators, has an important role in GI hypersensitivity reactions; once released from mast cells, it can easily reach the afferent sensory nerves nearby and activate neuron discharge, thus increasing visceral sensitization to painful stimuli (103). In line with this, treatment with mast cell stabilizers prevents lowering of pain threshold, which occurs during mucosal inflammation (90). According to the species, H1R, H2R or H3R subtypes have been involved in the alteration of visceral pain perception induced by histamine (104-107). As opposed to the early studies, it is now clear that H4Rs are expressed and are functionally active on neurons of the mammalian central and peripheral nervous system (52, 98, 108-110). To the best of our knowledge, no study has examined to date whether H4Rs are located on afferent fibers of the enteric nervous system; in view of the inhibitory effects of H4R antagonists in different pain models, it might be of interest to explore the effects of H4R ligands in models of visceral pain (65, 111-113).
6.5. Inflammation and immunity
Accumulating evidence has suggested that histamine plays a key role in inflammation, immediate hypersensitivity reaction and cellular and humoral immune response (28, 30, 41). Preformed or neosynthesized histamine is produced during inflammatory response in several GI disorders, such as food allergy, IBD and IBS, and exerts multiple regulatory effects through the activation of both H1Rs and H2Rs (32, 37, 41, 114-116). However, the efficacy of medical therapy based on the use of antihistamines or mast cell stabilizers is unproven (115). The recent discovery of H4Rs, mainly located in immune and inflammatory cells has further strengthened the role of histamine at this level. Given the ability of H4Rs to modulate the function of mast cells, T cells, dendritic cells and eosinophils, it is natural to foresee a therapeutic potential of H4R antagonists in inflammatory disorders of the GI tract. Indeed, both in vitro and in vivo studies provided evidence for a beneficial effect of H4R antagonists as anti-inflammatory agents (Tables 2 and 3). Histamine H4R antagonists were effective against the intestinal damage induced in rats by TNBS, a hapten which induces in rodents many of the macroscopic, histological and immunological hallmarks of the human IBD (60). In this assay, oral administration of JNJ7777120 produced a significant inhibition of macroscopic damage, neutrophil infiltration and the increase in TNFalpha and IL-6, two cytokines that play a critical role in the pathogenesis of the human disease (117-120). Other studies have confirmed the inhibitory effects of H4R antagonists on neutrophil influx into peritoneal cavity or into the pleural cavity (65, 121). JNJ7777120 was partially effective in reducing zymosan-induced peritonitis, a model of acute inflammation which is reported to be mast cell-dependent, since the neutrophil influx induced by zymosan is reduced in mast cell-deficient mice (64, 122). The observation that the H4R antagonist was ineffective in the peritonitis induced by thioglycollate (a mast cell-independent model) is consistent with the hypothesis than JNJ7777120 is acting on mast cells (64, 122). In line with this, analysis of peritoneal cell exudate in mice unraveled an expression of H4R mRNA higher in naive animals, as compared to genetically modified mice, devoid of mast cells, suggesting that resident mast cells may be the predominant H4R-expressing cell in the peritoneum (113).
Finally, the involvement of H4Rs in the ischemia/reperfusion-induced damage was recently reported in mice (123); this findings, however, were obtained with the H3/H4 receptor blocker thioperamide, thus the evidence for a specific involvement of H4Rs is lacking; in line with this, previous data obtained in rats showed that the effect of histamine on intestinal ischemia was related to activation of H1Rs (124).
6.6. Carcinogenesis
The stimulatory effect of histamine on tumor growth has been known for long time (31). High levels of HDC activity and high concentrations of histamine have been detected in both experimental and human tumours, such as breast cancer, melanoma, small cell lung carcinoma, endometrial cancer and colorectal carcinoma (38, 49, 125-129). In addition, histamine content was correlated with the presence of lymph node and/or distant metastasis in colorectal cancer (49). Histamine was reported to act also as an angiogenic factor and induce vascular endothelial growth factor (VEGF) production, thus influencing the process of tumour invasion and metastasis (130, 131). The tumour promoting effects of histamine appear to be predominantly mediated by H2Rs; in line with this, some encouraging results of clinical trials have shown increased survival of gastric and colon cancer patients after treatment with the H2R antagonists cimetidine and ranitidine (132-134).
The recent discovery that histamine H4R expression was detected in colorectal specimens has renewed the interest for the role of histamine in carcinogenesis and opened new horizons in this field. A recent study investigated the distribution of the different histamine receptor subtypes in the colorectal tumours compared to the normal mucosa, by different techniques such as RT-PCR, Western blot analysis and immunostaining (98). The study demonstrated the presence of H1R, H2R and H4R expression in adenoma and human colon carcinoma at protein level; in addition, in line with previous studies ruled out the presence of H3Rs in the human intestinal tissue (49, 51, 99). Histamine receptor expression pattern in neoplastic tissue was altered as compared to normal colonic mucosa, with significantly reduced expression of both H1Rs and H4Rs in tumour (98); this could favour H2R-mediated regulation of tumour cell growth. Further studies are required to clarify whether H4R downregulation has relevance in tumour progression and whether agonism at H4Rs combined to H2R antagonism would shift the process in the direction of tumour inhibition. It is of interest that H4R activation reduced cell proliferation in a pancreatic carcinoma cell line and in human hematopoietic progenitor cell (135, 136). Recently, however, it was reported that the H4R antagonist JNJ7777120 and the H2R antagonist zolantidine prevented the effects of histamine on cell proliferation, VEGF production and cyclooxygenase-2 (COX-2) induction in several colon cancer cell lines, without affecting basal cell proliferation (49). Collectively, these findings suggest that further studies are needed to assess the role of H4Rs on tumor cell growth.
7. SUMMARY AND PERSPECTIVE
Over the past few years research on histamine H4Rs has provided significant evidence for a role of this new receptor in a variety of histamine functions, emphasizing the concept that there is still much to learn about histamine and its versatile biology. The findings reviewed here strongly suggest that histamine H4Rs may participate in the GI effects of histamine; H4R expression was found in different cell types and can vary under pathological conditions characterized by inflammation and malignancies. The beneficial effects demonstrated by H4R antagonists in several models of GI mucosal damage, would lead to conclude that the H4R could be a potential target candidate in the therapy of functional GI diseases. However, further studies with more selective ligands are needed to characterize the GI H4R under both physiological and pathological conditions. This would be of utmost importance, when considering that H4R antagonists are being proposed as new anti-inflammatory/anti-allergic drugs and that most of the therapeutically available drugs for inflammation and pain are endowed with significant gastric and intestinal toxicity (137, 138).
8. ACKNOWLEDGEMENTS
The Authors acknowledge support from COST BM0806 (European Cooperation in Science and Technology).
9. REFERENCES
1. H.H. Dale and P.P. Laidlaw: The physiological action of β-imidazolyl-ethylamine. J Physiol 41, 318-344 (1910)
2. D. Bovet and A.M. Staub: Action protectrice des ethers phenoliques au cours de l'intoxication histaminique. CR Soc Biol (Paris) 124, 547-549 (1937)
3. J.W. Black, W.A.M. Duncan, G.J. Durant, C.R. Ganellin and M.E. Parsons: Definition and antagonism of histamine H2-receptors. Nature 236, 385-390 (1972)
doi:10.1038/236385a0
4. M. Feldman and M.E. Burton: Histamine2-receptor antagonists. Standard therapy for acid-peptic disease. First part. N Engl J Med 323, 1672-1680 (1990)
doi:10.1056/NEJM199012133232405
5. M. Feldman and M.E. Burton: Histamine2-receptor antagonists. Standard therapy for acid-peptic disease. Second part. N Engl J Med 323, 1749-1755 (1990)
doi:10.1056/NEJM199012203232507
6. J.M. Arrang, M. Garbarg and J.C. Schwartz: Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptors. Nature 302, 832-837 (1983)
doi:10.1038/302832a0
7. T. Nakamura, H. Itadani, Y. Hidaka, M. Ohta and K. Tanaka: Molecular cloning and characterization of a new human histamine receptor, HH4R. Biochem Biophys Res Commun 279, 615-620 (2000)
doi:10.1006/bbrc.2000.4008
8. T. Oda, N. Morikawa, Y. Saito, Y. Masuho and S. Matsumoto: Molecular cloning and characterization of a novel type of histamine receptor preferentially expressed in leukocytes. J Biol Chem 275, 36781-36786 (2000)
doi:10.1074/jbc.M006480200
9. C. Liu, X. Ma, X. Jiang, S.J. Wilson, C.L. Hofstra, J. Blevitt, J. Pyati, X. Li, W. Chai, N. Carruthers and T.W. Lovenberg: Cloning and pharmacological characterization of a fourth histamine receptor (H4) expressed in bone marrow. Mol Pharmacol 59, 420-426 (2001)
PMID:11179434
10. K.L. Morse, J. Behan, T.M. Laz, R.E. West Jr, S.A. Greenfeder, J.C. Anthes, S. Umland, Y. Wan, R.W. Hipkin, W. Gonsiorek, N. Shin, E.L. Gustafson, X. Qiao, S. Wang, J.A. Hedrick, J. Greene, M. Bayne and F.J. Monsma Jr: Cloning and characterization of a novel human histamine receptor. J Pharmacol Exp Ther 296, 1058-1066 (2001)
PMID:11181941
11. T. Nguyen, D.A. Shapiro, S.R. George, V. Setola, D.K. Lee, R. Cheng, L. Rauser, S.P. Lee, K.R. Lynch, B.L. Roth and B.F. O'Dowd: Discovery of a novel member of the histamine receptor family. Mol Pharmacol 59, 427-433 (2001)
PMID:11179435
12. Y. Zhu, D. Michalovich, H. Wu, K.B. Tan, G.M. Dytko, I.J. Mannan, R. Boyce, J. Alston, L.A. Tierney, X. Li, N.C. Herrity, L. Vawter, H.M. Sarau, R.S. Ames, C.M. Davenport, J.P. Hieble, S. Wilson, D.J. Bergsma and L.R. Fitzgerald: Cloning, expression and pharmacological characterization of a novel human histamine receptor. Mol Pharmacol 59, 434-441 (2001)
PMID:11179436
13. S. Celanire, M. Wijtmans, P. Talaga, R. Leurs and I.J. de Esch: Keynote review: histamine H3 receptor antagonists reach out for the clinic. Drug Discov Today 10, 1613-1627 (2005)
doi:10.1016/S1359-6446(05)03625-1
14. D. Vohora: The third Histamine Receptor: Selective Ligands as Potential Therapeutic Agents in CNS Disorders. CRC Press (Taylor and Francis Group), Boca Raton, FL (2008)
doi:10.1201/9781420053937
15. M.B. Passani, P. Blandina and F. Torrealba: H3 Rreceptor Miniseries: the histamine H3 receptor and eating behaviour. J Pharmacol Exp Ther (2010)
doi:10.1124/jpet.110.171306
PMCid:2802467
16. I.J. de Esch, R.L. Thurmond, A. Jongejan and R. Leurs: The histamine H4 receptor as a new therapeutic target for inflammation. Trends Pharmacol Sci 26, 462-469 (2005)
PMID:16054239
17. M. Zhang, R.L. Thurmond and P.J. Dunford: The histamine H4 receptor: a novel modulator of inflammatory and immune disorders. Pharmacol Ther 113, 594-606 (2007)
doi:10.1016/j.pharmthera.2006.11.008
18. R.L. Thurmond, E.W. Gelfand and P.J. Dunford: The role of histamine H1 and H4 receptors in allergic inflammation: the search for new antihistamines. Nat Rev Drug Discov 7, 41-53 (2008)
doi:10.1038/nrd2465
PMID:18172439
19. R. Leurs, P.L. Chazot, F.C. Shenton, H.D. Lim and I.J.P. de Esch: Molecular and biochemical pharmacology of the histamine H4 receptor. Br J Pharmacol 157, 14-23 (2009)
doi:10.1111/j.1476-5381.2009.00250.x
PMID:19413568 PMCid:2697796
20. R.A. Smits, R. Leurs and I.J. de Esch: Major advances in the development of histamine H4 receptor ligands. Drug Discov Today 14, 745-753 (2009)
doi:10.1016/j.drudis.2009.05.007
PMID:19477292
21. E. Zampeli and E. Tiligada: The role of histamine H4 receptor in immune and inflammatory disorders. Br J Pharmacol 157, 24-33 (2009)
doi:10.1111/j.1476-5381.2009.00151.x
PMID:19309354
PMCid:2697784
22. R. Hakanson, C. Wahlestedt, L. Westlin, S. Vallgren and F. Sundler: Neuronal histamine in the gut wall releasable by gastrin and cholecystokin. Neurosci Lett 42, 305-310 (1983)
doi:10.1016/0304-3940(83)90279-3
23. R. Hakanson, D. Chen, K. Andersson, H.J. Monstein, C.M. Zhao, B. Ryberg, F. Sundler and H. Mattsson: The biology and physiology of the ECL cell. Yale J Biol Med 67, 123-134 (1994)
PMID:7502521
PMCid:2588926
24. B. Hunyady, A. Zolyomi, B.J. Hoffman and E. Mezey: Gastrin-producing endocrine cells: a novel source of histamine in the rat stomach. Endocrinology 139, 4404-4415 (1998)
doi:10.1210/en.139.10.4404
PMID:9751525
25. E. Ekblad, C. Wahlestedt, R. Hakanson, F. Sundler, T. Watanabe and H. Wada: Is histamine a neurotransmitter in the gut? Evidence from histidine decarboxylase immunocytochemistry. Acta Physiol Scand 123, 225-227 (1985)
doi:10.1111/j.1748-1716.1985.tb07582.x
PMID:2858961
26. P. Panula, M. Kaartinen, M. Macklin and E. Costa: Histamine-containing peripheral neuronal and endocrine systems. J Histochem Cytochem 33, 933-941 (1985)
PMID:3894504
27. M. Shiraishi, N. Hirasawa, S. Oikawa, Y. Kobayashi and K. Ohuchi: Analysis of histamine-producing cells at the late phase of allergic inflammation in rats. Immunology 99, 600-606 (2000)
doi:10.1046/j.1365-2567.2000.00986.x
PMID:10792508
PMCid:2327195
28. D. MacGlashan Jr: Histamine: A mediator of inflammation. J Allergy Clin Immunol 112 Suppl 4, S53-S59 (2003)
doi:10.1016/S0091-6749(03)01877-3
29. M. Dy and E. Schneider: Histamine-cytokine connection in immunity and hematopoiesis. Cytokine Growth Factor Rev 15, 393-410 (2004)
doi:10.1016/j.cytogfr.2004.06.003
30. M. Jutel, M. Akdis and C.A. Akdis: Histamine, histamine receptors and their role in immune pathology. Clin Exp Allergy 39, 1786-1800 (2009)
doi:10.1111/j.1365-2222.2009.03374.x
31. V.A. Medina and E.S. Rivera: Histamine receptors and cancer pharmacology. Br J Pharmacol 161, 755-767 (2010)
doi:10.1111/j.1476-5381.2010.00961.x
PMID:20636392
32. J.D. Wood: Histamine, mast cells, and the enteric nervous system in the irritable bowel syndrome, enteritis, and food allergies. Gut 55, 445-447 (2006)
PMID:7687574
33. C. Prinz, M. Kajimura, D.R. Scott, F. Mercier, H.F. Helander and G. Sachs: Histamine secretion from rat enterochromaffinlike cells. Gastroenterology 105, 449-461 (1993)
34. E. Lindstrom, D. Chen, P. Norlen, K. Andersson and R. Hakanson: Control of gastric acid secretion: the gastrin-ECL cell-parietal cell axis. Comp Biochem Physiol A Mol Integr Physiol 128, 505-514 (2001)
doi:10.1016/S1095-6433(00)00331-7 PMid:7549499
35. M. Raithel, M. Matek, H.W. Baenkler, W. Jorde and E.G. Hahn: Mucosal histamine content and histamine secretion in Crohn's disease, ulcerative colitis and allergic enteropathy. Int Arch Allergy Immunol 108, 127-133 (1995) doi:10.1159/000237129
36. J.L. Reynolds, J. Akhter, W.J. Adams and D.L. Morris: Histamine content in colorectal cancer. Are there sufficient levels of histamine to affect lymphocyte function? Eur J Surg Oncol 23, 224-227 (1997)
doi:10.1016/S0748-7983(97)92388-X PMid:14988823
37. G. Barbara, V. Stanghellini, R. De Giorgio, C. Cremon, G.S. Cottrell, D. Santini, G. Pasquinelli, A.M. Morselli-Labate, E.F. Grady, N.W. Bunnett, S.M. Collins and R. Corinaldesi: Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 126, 693-702 (2004)
doi:10.1053/j.gastro.2003.11.055
PMID:15928846
38. E. Masini, V. Fabbroni, L. Giannini, L. Vannacci, L. Messerini, F. Perna, C. Cortesini and F. Cianchi: Histamine and histidine decarboxylase up-regulation in colorectal cancer: correlation with tumor stage. Inflamm Res 54 Suppl 1, S80-S81 (2005) doi:10.1007/s00011-004-0437-3
39. G. Bertaccini and G. Coruzzi: Histamine receptors in the digestive system. In: The Histamine receptor. Eds. Schwartz JC and Haas HL, Wiley-Liss, NY, 193-230 (1992) PMid:17031123
40. M.L. Schubert: Gastric secretion. Curr Opin Gastroenterol 16, 463-468 (2000)
doi:10.1097/00001574-200011000-00002
PMID:16531524 PMCid:1856149
41. M. Jutel, T. Watanabe, M. Akdis, K. Blaser and C.A. Akdis: Immune regulation by histamine. Curr Opinion Immunol 14, 735-740 (2002)
doi:10.1016/S0952-7915(02)00395-3
42. G.J. Molderings: Mast cell function in physiology and pathophysiology. BIOTREND Rev 5, 1-9 (2010)
43. M. Kidd, L.H. Tang, K. Miu, G.P. Lawton, A. Sandor and I.M. Modlin: Autoregulation of enterochromaffin-like cell histamine secretion via the histamine 3 receptor subtype. Yale J Biol Med 69, 9-19 (1996)
PMID:9041685
PMCid:2588967
44. G. Coruzzi, E. Poli, G. Morini and G. Bertaccini: The histamine H3 receptor. In: Molecular Targets for Drug Development: GI Diseases. Eds.: Gaginella TS, Guglietta A, Humana Press, Totowa, NY, 239-267 (2000)
45. M.E. Parsons and C.R. Ganellin: Histamine and its receptors. Br J Pharmacol 147 Suppl 1, S127-S135 (2006)
doi:10.1038/sj.bjp.0706440
PMID:16402096
PMCid:1760721
46. G. Coruzzi and M. Adami: Peripheral actions and therapeutic potential in periphery. In: The third Histamine Receptor: Selective Ligands as Potential Therapeutic Agents in CNS Disorders. Ed.: Vohora D, CRC Press, Taylor and Francis Group, NY, 167-209 (2008)
doi:10.1201/9781420053937.ch6
47. F. Coge, S.P. Guenin, H. Rique, J.A. Boutin and J.P. Galizzi: Structure and expression of the human histamine H4-receptor gene. Biochem Biophys Res Commun 284, 301-309 (2001)
doi:10.1006/bbrc.2001.4976
PMID:11394877
48. T. Oda, S. Matsumoto, Y. Masuho, J. Takasaki, M. Matsumoto, M. Kamohara, T. Saito, T. Ohishi, T. Soga, H. Hiyama, H. Matsushime and K. Furuichi: cDNA cloning and characterization of porcine histamine H4 receptor. Biochim Biophys Acta 1575, 135-138 (2002)
PMID:12020829
49. F. Cianchi, C. Cortesini, N. Schiavone, F. Perna, L. Magnelli, E. Fanti, D. Bani, L. Messerini, V. Fabbroni, G. Perigli, S. Capaccioli and E. Masini: The role of cyclooxygenase-2 in mediating the effects of histamine on cell proliferation and vascular endothelial growth factor production in colorectal cancer. Clin Cancer Res 11, 6807-6815 (2005)
doi:10.1158/1078-0432.CCR-05-0675
PMID:16203768
50. T. Oda, S. Matsumoto, M. Matsumoto, J. Takasaki, M. Kamohara, T. Soga, H. Hiyama, M. Kobori and M. Katoh: Molecular cloning of monkey histamine H4 receptor. J Pharmacol Sci 98, 319-322 (2005)
doi:10.1254/jphs.SC0050033
PMID:15968139
51. L.E. Sander, A. Lorentz, G. Sellge, M. Coeffier, M. Neipp, T. Veres, T. Frieling, P.N. Meier, M.P. Manns and S.C. Bischoff: Selective expression of histamine receptors H1R, H2R, and H4R, but not H3R, in the human intestinal tract. Gut 55, 498-504 (2006)
52. P.L. Chazot, F.C. Shenton, H. Waldvogel, D. Grandi and G. Morini: The H4 histamine receptor is expressed in both the human CNS and rodent PNS. European Histamine Research Society, 36th Meeting, p.27 (2007)
PMID:18258331
53. K. Boer, E. Helinger, A. Helinger, P. Pocza, Z. Pos, P. Demeter, Z. Baranyai, K. Dede, Z. Darvas and A. Falus: Decreased expression of histamine H1 and H4 receptors suggests disturbance of local regulation in human colorectal tumours by histamine. Eur J Cell Biol 87, 227-236 (2008)
doi:10.1016/j.ejcb.2007.12.003 PMid:18639542
54. W. Jiang, H.D. Lim, M. Zhang, P. Desai, H. Dai, P.M. Colling, R. Leurs and R.L. Thurmond: Cloning and pharmacological characterization of the dog histamine H4 receptor. Eur J Pharmacol 592, 26-32 (2008)
doi:10.1016/j.ejphar.2008.06.095
PMID:18345490
55. G. Morini, G. Becchi, F.C. Shenton, P.L. Chazot and D. Grandi: Histamine H3 and H4 receptors are expressed on distinct endocrine cell type in the rat fundic mucosa. Inflamm Res 57 Suppl 1, S57-S58 (2008) doi:10.1007/s00011-007-0628-9 PMid:18644879 PMCid:2546858
56. T.L. Sutton, A. Zhao, K.B. Madden, J.E. Elfrey, B.A. Tuft, C.A. Sullivan, J.F. Urban Jr and T. Shea-Donohue: Anti-inflammatory mechanisms of enteric Heligmosomoides polygyrus infection against trinitrobenzene sulfonic acid-induced colitis in a murine model. Infect Immun 76, 4772-4782 (2008)
doi:10.1128/IAI.00744-07
PMID:18191952
57. S. Yu, E. Stahl, Q. Li and A. Ouyang: Antigen inhalation induces mast cells and eosinophils infiltration in the guinea pig esophageal epithelium involving histamine-mediated pathway. Life Sci 82, 324-330 (2008)
doi:10.1016/j.lfs.2007.12.002
PMID:19413570
PMCid:2697788
58. M.I. Strakhova, C.A. Cuff, A.M. Manelli, T.L. Carr, D.G. Witte, J.L. Baranowski, T.A. Vortherms, T.R. Miller, L. Rundell, M.J. McPherson, R.M. Adair, A.A. Brito, B.M. Bettencourt, B.B. Yao, J.M. Wetter, K.C. Marsh, H. Liu, M.D. Cowart, J.D. Brioni and T.A. Esbenshade: In vitro and in vivo characterization of A-940894: a potent histamine H4 receptor antagonist with anti-inflammatory properties. Br J Pharmacol 157, 44-54 (2009)
doi:10.1111/j.1476-5381.2009.00236.x
PMID:19277450
59. K. Takagaki, S. Osawa, Y. Horio, T. Yamada, Y. Hamaya, Y. Takayanagi, T. Furuta, A. Hishida and M. Ikuma: Cytokine responses of intraepithelial lymphocytes are regulated by histamine H2 receptor. J Gastroenterol 44, 285-296 (2009)
doi:10.1007/s00535-009-0019-9
60. C.O. Elson, R.B. Sartor, G.S. Tennyson and R.H. Riddell: Experimental models of inflammatory bowel disease. Gastroenterology 109, 1344-1367 (1995)
doi:10.1016/0016-5085(95)90599-5
61. A.K. Kumawat, Y.Y. Gotlind, M.F. Fredin, R. Willen, H. Strid and E.H. Hornquist: Expression patterns of histamine receptors in the Gi2alpha-deficient mouse model of colitis. In: European Histamine Research Society, 39th Annual Meeting, p.93 (2010)
PMID:19441913
62. R. Kiss and G.M. Keseru: Histamine H4 receptor ligands and their potential therapeutic applications. Expert Opin Ther Pat 19, 119-135 (2009)
doi:10.1517/13543770802691085
PMID:16299042
PMCid:1856162
63. J.A. Jablonowski, C.A. Grice, W. Chai, C.A. Dvorak, J.D. Venable, A.K. Kwok, K.S. Ly, J. Wei, S.M. Baker, P.J. Desai, W. Jiang, S.J. Wilson, R.L. Thurmond, L. Karlsson, J.P. Edwards, T.W. Lovenberg and N.I. Carruthers: The first potent and selective non-imidazole human histamine H4 receptor antagonists. J Med Chem 46, 3957-3960 (2003)
doi:10.1021/jm0341047
PMID:12954048
64. R.L. Thurmond, P.J. Desai, P.J. Dunford, W.P. Fung-Leung, C.L. Hofstra, W. Jiang, S. Nguyen, J.P. Riley, S. Sun, K.N. Williams, J.P. Edwards and L. Karlsson: A potent and selective histamine H4 receptor antagonist with anti-inflammatory properties. J Pharmacol Exp Ther 309, 404-413 (2004)
doi:10.1124/jpet.103.061754
PMID:14722321
65. H. Liu, R.J. Altenbach, T.L. Carr, P. Chandran, G.C. Hsieh, L.G. Lewis, A.M. Manelli, I. Milicic, K.C. Marsh, T.R. Miller, M.I. Strakhova, T.A. Vortherms, B.D. Wakefield, J.M. Wetter, D.G Witte, P. Honore, T.A. Esbenshade, J.D. Brioni and M.D. Cowart: cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro (2,3-h)quinazolin-2-amine (A-987306), a new histamine H4R antagonist that blocks pain responses against carrageenan-induced hyperalgesia. J Med Chem 51, 7094-7098 (2008)
doi:10.1021/jm8007618
PMID:18983139
66. H. Engelhardt, R.A. Smits, R. Leurs, E. Haaksma and I.J. De Esch: A new generation of anti-histamines: Histamine H4 receptor antagonists on their way to the clinic. Curr Opin Drug Discov Devel 12, 628-643 (2009)
PMID:19736622
67. H.D. Lim, R.M. van Rijn, P. Ling, R. Bakker, R. Thurmond and R. Leurs: Evaluation of histamine H1-, H2-, and H3-receptor ligands at the human histamine H4 receptor: identification of 4-methylhistamine as the first potent and selective H4 receptor agonist. J Pharmacol Exp Ther 314, 1310-1321 (2005)
doi:10.1124/jpet.105.087965
PMID:15947036
68. H.D. Lim, R.A. Smits, R.A. Bakker, C.M. van Dam, I.J. de Esch and R. Leurs: Discovery of S-(2-guanidylethyl)-isothiourea (VUF 8430) as a potent nonimidazole H4 receptor agonist. J Med Chem 49, 6650-6651 (2006)
doi:10.1021/jm060880d
PMID:17154494
69. T. Kenakin: Pharmacological proteus? Trends Pharmacol Sci 16, 256-258 (1995)
doi:10.1016/S0165-6147(00)89037-9
70. N.P. Clarke, C.D. Brown, C. Lane, C. Mowbray, H.D. Lim, R. Leurs, E. Schenck, C. Perros-Huguet and M. Yeadon: PF-2988403- an 'H4 antagonist' demostrating the full range of in vitro pharmacologies which translate in vivo in the rat. In: European Histamine Research Society, 37thAnnual Meeting, Abstract No.07, p.34 (2008)
71. G. Coruzzi, M. Adami, C. Pozzoli, R. Smits, I. de Esch and R. Leurs: Gastroprotective effects of histamine H4 receptor ligands in rodent ulcer models. Br J Pharmacol 7, 150P (2010)
72. D. Neumann, S. Beermann and R. Seifert: Does the histamine H4 receptor have a pro- or anti-inflammatory role in murine bronchial asthma? Pharmacology 85, 217-223 (2010)
doi:10.1159/000285088
PMID:20215812
73. N. Adachi, K. Liu, A. Motoki, M. Nishibori and T. Arai: Suppression of ischemia/reperfusion liver injury by histamine H4 receptor stimulation in rats. Eur J Pharmacol 544, 181-187 (2006)
doi:10.1016/j.ejphar.2006.06.053
PMID:16860312
74. W.W. Pawlik, R. Obuchowicz, M.W. Pawlik, R. Sendur, J. Biernat, T. Brzozowski, and S.J. Konturek: Histamine H3 receptors modulate reactive hyperemia in rat gut. J Physiol Pharmacol 55, 651-661 (2004)
PMID:15381834
75. A. Rydning, O. Lying, B.L. Adamsen, S. Falkmer, A.K. Sandvik and J.E. Gronbech: Mast cells are involved in the gastric hyperemic response to acid back diffusion via release of histamine. Am J Physiol Gastrointest Liver Physiol 280, G1061-G1069 (2001)
76. N. Terzioglu, R.M. van Rijn, R.A. Bakker, I.J. de Esch and R. Leurs: Synthesis and structure-activity relationships of indole and benzimidazole piperazines as histamine H4 receptor antagonists. Bioorg Med Chem Lett 14, 5251-5256 (2004)
doi:10.1016/j.bmcl.2004.08.035
77. H.D. Lim, M. Adami, E. Guaita, T. Werfel, R.A. Smits, I.J. de Esch, R.A. Bakker, R. Gutzmer, G. Coruzzi and R. Leurs: Pharmacological characterization of the new histamine H4 receptor agonist VUF 8430. Br J Pharmacol 157, 34-43 (2009)
doi:10.1111/j.1476-5381.2009.00200.x
PMID:19413569
PMCid:2697786
78. G. Morini, D. Grandi and G. Bertaccini: (R)-alpha-methylhistamine inhibits ethanol-induced gastric lesions in the rat: involvement of histamine H3 receptors? Digestion 56, 145-152 (1995)
doi:10.1159/000201234
PMID:7750668
79. G. Morini, D. Grandi, M. Krause, and W. Schunack: Gastric mucosal injury by nonsteroidal anti-inflammatory drugs is reduced by (R)-aplha-methylhistamine and its pro-drugs in the rat. Inflamm Res 46 Suppl 1, S101-102 (1997) doi:10.1007/s000110050117
80. G. Morini, D. Grandi, H. Stark and W. Schunack: Histamine H3-receptor antagonists inhibit gastroprotection by (R)-alpha-methylhistamine in the rat. Br J Pharmacol 129, 1597-1600 (2000)
doi:10.1038/sj.bjp.0703249
PMID:10780963
PMCid:1572006
81. Z. Warzecha, A. Dembinski, T. Brzozowski, P. Ceranowicz, R. Pajdo, J. Niemiec, D. Drozdowicz, M. Mitis-Musiol and S.J. Konturek: Gastroprotective effect of histamine and acid secretion on ammonia-induced gastric lesions in rats. Scand J Gastroenterol 35, 916-924 (2000)
doi:10.1080/003655200750022959
PMID:11063149
82. S. Kwiecien, T. Brzozowski, P.C. Konturek, S.J. Konturek, M. Pawlik, R. Pajdo, D. Drozdowicz, A. Ptak and E.G. Hahn: Effect of central and peripheral actions of histamine and its metabolite N-alpha methyl histamine on gastric acid secretion and acute gastric lesions. J Physiol Pharmacol 52, 625-638 (2001) PMid:11787763
83. A. Dembinski, Z. Warzecha, P. Ceranowicz, T. Brzozowski, M. Dembinski, S.J. Konturek and W.W. Pawlik: Role of capsaicin-sensitive nerves and histamine H1, H2, and H3 receptors in the gastroprotective effect of histamine against stress ulcers in rats. Eur J Pharmacol 508, 211-221 (2005)
doi:10.1016/j.ejphar.2004.11.059
PMID:15680274
84. G. Morini, D. Grandi and W. Schunack: Ligands for histamine H3 receptors modulate cell proliferation and migration in rat oxyntic mucosa. Br J Pharmacol 137, 237-244 (2002)
doi:10.1038/sj.bjp.0704853
PMID:12208781
PMCid:1573479
85. D. Grandi, W. Schunack and G. Morini: Epithelial cell proliferation is promoted by the histamine H3 receptor agonist (R)-alpha-methylhistamine throughout the rat gastrointestinal tract. Eur J Pharmacol 538, 141-147 (2006)
doi:10.1016/j.ejphar.2006.03.049
PMID:16682020
86. G. Morini, H. Timmerman, W. Schunack and D. Grandi: Agonists for the histamine H3-receptor differ in their gastroprotective activity in the rat. Inflamm Res 51 Suppl 1, S75-S76 (2002)
87. M. Adami, G. Coruzzi, E. Guaita, I.J.P. de Esch and R. Leurs: Antiinflammatory, analgesic and gastroprotective effects of the novel and selective histamine H4-receptor antagonist VUF5949. In: European Histamine Research Society, 34th Annual Meeting, p.47 (2005)
88. T.L. Peeters: Ghrelin: a new player in the control of gastrointestinal functions. Gut 54, 1638-1649 (2005)
PMID:20145426
89. M. Adami, C. Pozzoli, R. Leurs, H. Stark and Coruzzi G: Histamine H3 receptors are involved in the protective effect of gherlin on against HCl-induced gastric damage in rats. Pharmacology (2010)
doi: 10.1159/000320110
PMID:17457962
90. J.D. Wood: Neuropathophysiology of functional gastrointestinal disorders. World J Gastroenterol 13, 1313-1332 (2007)
PMID:16227363
PMCid:1774760
91. J.H. Zavecz and T.O. Yellin: Histamine receptors in the myenteric plexus-longitudinal muscle of the guinea pig ileum: H1- and H2-receptor-mediated potentiation of the contractile response to electrical stimulation. J Pharmacol Exp Ther 223, 177-182 (1982)
PMID:6126581
92. S.J. Keely, W.A. Stack, D.P. O'Donoghue and A.W. Baird: Regulation of ion transport by histamine in the human colon. Eur J Pharmacol 279, 203-209 (1995)
doi:10.1016/0014-2999(95)00156-F
93. W.A. Stack, S.J. Keely, D.P. O'Donoghue and A.W. Baird: Immune regulation of human colon electrolyte transport in vitro. Gut 36, 395-400 (1995)
94. H. Schworer, A. Reimann, G. Ramadori and K. Racke: Characterization of H3 receptors inhibiting 5-HT release from porcine enterochromaffin cells: further evidence for H3 receptor heterogeneity. Naunyn Schmiedebergs Arch Pharmacol 350, 375-379 (1994)
doi:10.1007/BF00178954
PMID:19271139
95. C. Pozzoli, M. Adami, R.A. Smits and G. Coruzzi: Effect of histamine H4 receptor ligands on cholinergic neurotransmission of the rat duodenum. Inflamm Res 58 Suppl 1, S59-S60 (2009) doi:10.1007/s00011-009-2012-4
96. T. Frieling, H.J. Cooke and J.D. Wood: Histamine receptors on submucous neurons in the guinea pig colon. Am J Physiol 264, G74-G80 (1993)
PMID:15300595
97. J.D. Wood: Enteric neuroimmunophysiology and pathophysiology. Gastroenterology 127, 635-657 (2004)
doi:10.1053/j.gastro.2004.02.017
PMID:17627982
PMCid:2277025
98. E. Breunig, K. Michel, F. Zeller, S. Seidl, C.W. Weyhern and M. Schemann: Histamine excites neurones in the human submucous plexus through activation of H1, H2, H3 and H4 receptors. J Physiol 583, 731-742 (2007)
doi:10.1113/jphysiol.2007.139352
PMID:11218065
99. M. Hemedah, R. Loiacono, I.M. Coupar and F.J. Mitchelson: Lack of evidence for histamine H3 receptor function in rat ileum and human colon. Naunyn Schmiedebergs Arch Pharmacol 363, 133-138 (2001)
doi:10.1007/s002100000345
100. A. Aly, F. Barany, B. Kollberg, U. Monsen, O. Wisen and C. Johansson: Effect of an H2-receptor blocking agent on diarrhoeas after extensive small bowel resection in Crohn's disease. Acta Med Scand 207, 119-122 (1980)
doi:10.1111/j.0954-6820.1980.tb09688.x
PMID:16956793
101. J. Santos, C. Alonso, M. Guilarte, M. Vicario and J.R. Malagelada: Targeting mast cells in the treatment of functional gastrointestinal diseases. Curr Opin Pharmacol 6, 541-546 (2006)
doi:10.1016/j.coph.2006.08.001
PMID:6693007
102. L. Bueno and J. Fioramonti: Visceral perception: inflammatory and non-inflammatory mediators. Gut 51 Suppl. 1, i19-i23 (2002)
103. M.H. Perdue, M. Chung and D.G. Gall: Effect of intestinal anaphylaxis on gut function in the rat. Gastroenterology 86, 391-397 (1984)
104. G.N. Akoev, L.V. Filippova and N.O. Sherman: Mast cell mediators excite the afferents of cat small intestine. Neuroscience 71, 1163-1166 (1996)
doi:10.1016/0306-4522(95)00479-3
105. L.W. Fu, H.L. Pan and J.C. Longhurst: Endogenous histamine stimulates ischaemically sensitive abdominal visceral afferents through H1 receptors. Am J Physiol 273, H2726-H2737 (1997)
PMID:10581320
PMCid:2269676
106. M.E. Kreis, W. Haupt, A.J. Kirkup and D. Grundy: Histamine sensitivity of mesenteric afferent nerves in the rat jejunum. Am J Physiol 275, G675-G680 (1998)
PMID:15274415
107. A.M. Brunsden and D. Grundy: Sensitization of visceral afferents to bradykinin in rat jejunum in vitro. J Physiol 521, 517-527 (1999)
doi:10.1111/j.1469-7793.1999.00517.x
PMID:19046950
108. M. Nakaya, N. Takeuchi and K. Kondo: Immunohistochemical localization of histamine receptor subtypes in human inferior turbinates. Ann Otol Rhinol Laryngol 113, 552-557 (2004)
PMID:19413571 PMCid:2697783
109. M.I. Strakhova, A.L. Nikkel, A.M. Manelli, G.C. Hsieh, T.A. Esbenshade, J.D. Brioni and R.S. Bitner: Localization of histamine H4 receptors in the central nervous system of human and rat. Brain Res 1250, 41-48 (2009)
doi:10.1016/j.brainres.2008.11.018
PMID:17382315
110. W.M. Connelly, F.C. Shenton, N. Lethbridge, R. Leurs, H.J. Waldvogel, R.L. Faull, G. Lees and P.L. Chazot: The histamine H4 receptor is functionally expressed on neurons in the mammalian CNS. Br J Pharmacol 157, 55-63 (2009)
doi:10.1111/j.1476-5381.2009.00227.x
PMID:18817367
111. G. Coruzzi, M. Adami, E. Guaita, I.J. de Esch and R. Leurs: Antiinflammatory and antinociceptive effects of the selective histamine H4-receptor antagonists JNJ7777120 and VUF6002 in a rat model of carrageenan-induced acute inflammation. Eur J Pharmacol 563, 240-244 (2007)
doi:10.1016/j.ejphar.2007.02.026
PMID:20004681
112. M.D. Cowart, R.J. Altenbach, H. Liu, G.C. Hsieh, I. Drizin, I. Milicic, T.R. Miller, D.G. Witte, N. Wishart, S.R. Fix-Stenzel, M.J. McPherson, R.M. Adair, J.M. Wetter, B.M. Bettencourt, K.C. Marsh, J.P. Sullivan, P. Honore, T.A. Esbenshade and J.D. Brioni: Rotationally constrained 2,4-diamino-5,6-disubstituted pyrimidines: a new class of histamine H4 receptor antagonists with improved druglikeness and in vivo efficacy in pain and inflammation models. J Med Chem 51, 6547-6557 (2008)
doi:10.1021/jm800670r
PMID:1690156
113. G.C. Hsieh, P. Chandran, A.K. Salyers, M. Pai, C.Z. Zhu, E.J. Wensink, D.G. Witte, T.R. Miller, J.P. Mikusa, S.J. Baker, J.M. Wetter, K.C. Marsh, A.A Hancock, M.D. Cowart, T.A. Esbenshade, J.D. Brioni and P. Honore: H4 receptor antagonism exhibits anti-nociceptive effects in inflammatory and neuropathic pain models in rats. Pharmacol Biochem Behav 95, 41-50 (2010)
doi:10.1016/j.pbb.2009.12.004
PMID:15825090
114. L. Knutson, O. Ahrenstedt, B. Odlind and R. Hallgren: The jejunal secretion of histamine is increased in active Crohn's disease. Gastroenterology 98, 849-854 (1990)
PMID:17490952
115. S. Bischoff and S.E. Crowe: Gastrointestinal food allergy: new insights into pathophysiology and clinical perspectives. Gastroenterology 128, 1089-1113 (2005)
doi:10.1053/j.gastro.2004.08.015
116. L. Maintz and N. Novak: Histamine and histamine intolerance. Am J Clin Nutr 85, 1185-1196 (2007)
PMID:16213481
117. C. Fiocchi: Inflammatory bowel disease: etiology and pathogenesis. Gastroenterology 115, 182-205 (1998)
doi:10.1016/S0016-5085(98)70381-6
118. C. Varga, K. Horvath, A. Berko, R.L. Thurmond, P.J. Dunford and B.J. Whittle: Inhibitory effects of histamine H4 receptor antagonists on experimental colitis in the rat. Eur J Pharmacol 522, 130-138 (2005) PMid:17806163
119. P.J. Dunford, C. Varga, R.L. Thurmond and B.J. Whittle: Histamine H4 receptor antagonism attenuates toll-like receptor signaling and inhibits experimental colitis in the rat. Gastroenterology 130, W1597 (2006) PMid:14551291
120. W.A. Fogel, J. Jochem and A. Lewinski: Influence of the H3/H4 receptor antagonist, thioperamide on regional haemodinamics in rats with trinitrobenzene sulfonic acid-induced colitis. Inflamm Res 56 Suppl 1, S21-S22 (2007)
doi:10.1007/s00011-006-0510-1
PMID:9973430
121. K. Takeshita, K. Sakai, K.B. Bacon and F. Gantner: Critical role of histamine H4 receptor in leukotriene B4 production and mast cell-dependent neutrophil recruitment induced by zymosan in vivo. J Pharmacol Exp Ther 307, 1072-1078 (2003)
doi:10.1124/jpet.103.057489
122. M.N. Ajuebor, A.M. Das, L. Virag, R.J. Flower, C. Szabo and M. Perretti: Role of resident peritoneal macrophages and mast cells in chemokine production and neutrophil migration in acute inflammation: evidence for an inhibitory loop involving endogenous IL-10. J Immunol 162, 1685-1691 (1999)
PMID:7523223
123. P. Ghizzardi, T. Gobbetti, S. Bertoni, F. Saccani, L. Flammini, V. Ballabeni and E. Barocelli: Histamine H4 receptor antagonism and mesenteric ischemia/reperfusion injury in mice. Gastroenterology 136 Suppl 1, A-397 2009)
doi:10.1016/S0016-5085(09)61826-6
124. S. Tsunada, K. Fujimoto, Y. Gotoh, T. Sakai, M. Kang, T. Sakata, D.N. Granger and P. Tso: Role of histamine receptors in intestinal repair after ischemia-reperfusion in rats. Gastroenterology 107, 1297-1304 (1994)
125. R. Chandra and A.K. Ganguly: Diamineoxidase activity and tissue histamine content of human skin, breast and rectal carcinoma. Cancer Lett 34, 207-212 (1987)
doi:10.1016/0304-3835(87)90012-7
126. M. Garcia-Caballero, E. Neugebauer, F. Rodriguez, I. Nunez de Castro and C. Vara-Thorbeck: Histamine synthesis and content in benign and malignant breast tumours. Its effect on other host tissues. Surg Oncol 3, 167-173 (1994)
doi:10.1016/0960-7404(94)90046-9
PMID:12000707
PMCid:1850890
127. A. Falus, H. Hegyesi, E. Lazar-Molnar, Z. Pos, V. Laszlo and Z. Darvas: Paracrine and autocrine interactions in melanoma: histamine is a relevant player in local regulation. Trends Immunol 22, 648-652 (2001)
doi:10.1016/S1471-4906(01)02050-6
128. L. Graff, M. Frungieri, R. Zannar, A. Pohlinger, C. Prinz and M. Gratzl: Expression of histidine decarboxylase and synthesis of histamine by human small cell lung carcinoma. Am J Pathol 160, 1561-1565 (2002)
PMID:7511407
129. V. Medina, M. Croci, E. Crescenti, N. Mohamad, F. Sanchez-Jimenez, N. Massari, M. Nunez, G. Cricco, G. Martin, R. Bergoc and E. Rivera: The role of histamine in human mammary carcinogenesis: H3 and H4 receptors as potential therapeutic targets for breast cancer treatment. Cancer Biol Ther 7, 28-35 (2008)
doi:10.4161/cbt.7.1.5123
PMID:11724747
PMCid:1573073
130. J. Sorbo, A. Jakobsson and K. Norrby: Mast-cell histamine is angiogenic through receptors for histamine1 and histamine2. Int J Exp Pathol 75, 43-50 (1994)
131. A.K. Ghosh, N. Hirasawa and K. Ohuchi: Enhancement by histamine of vascular endothelial growth factor production in granulation tissue via H2 receptor. Br J Pharmacol 134, 1419-1428 (2001)
doi:10.1038/sj.bjp.0704372
PMID:10888265
132. W.J. Adams and D.L. Morris: Short-course cimetidine and survival with colorectal cancer. Lancet 344, 1768-1769 (1994)
doi:10.1016/S0140-6736(94)92907-6
PMID:12390384
133. E. Bolton, J. King and D.L. Morris: H2-antagonists in the treatment of colon and breast cancer. Semin Cancer Biol 10, 3-10 (2000)
doi:10.1006/scbi.2000.0301
PMID:18345506
134. H.J. Nielsen, U. Christensen, F. Moesgaard and H. Kehlet: Ranitidine as adjuvant treatment in colorectal cancer. Br J Surg 89, 1416-1422 (2002)
doi:10.1046/j.1365-2168.2002.02223.x
PMID:19662098
PMCid:2720606
135. G.P. Cricco, N.A. Mohamad, L.A. Sambuco, F. Genre, M. Croci, A.S. Gutierrez, V.A. Medina, R.M. Bergoc, E.S. Rivera and G.A. Martin: Histamine regulates pancreatic carcinoma cell growth through H3 and H4 receptors. Inflamm Res 57 Suppl 1, S23-S24 (2008)
doi:10.1007/s00011-007-0611-5
PMID:15464050
136. A.F. Petit-Bertron, F. Machavoine, M.P. Defresne, M. Gillard, P. Chatelain, P. Mistry, E. Schneider and M. Dy: H4 histamine receptors mediate cell cycle arrest in growth factor-induced murine and human hematopoietic progenitor cells. PLoS ONE, 4, e6504 (2009)
doi:10.1371/journal.pone.0006504
PMID:18923189
137. B.J. Whittle: Mechanisms underlying intestinal injury induced by anti-inflammatory COX inhibitors. Eur J Pharmacol 500, 427-439 (2004) doi:10.1016/j.ejphar.2004.07.042 PMid:7698700 PMCid:1382453
138. J.L. Wallace: Prostaglandins, NSAIDs, and gastric mucosal protection: why doesn't the stomach digest itself? Physiol Rev 88, 1547-1565 (2008)
doi:10.1152/physrev.00004.2008
Abbreviations: ANOVA: Analysis of variance; COX-2: Cyclooxygenase-2; ECL: enterochromaffin like; GI: gastrointestinal; H1R: Histamine H1 receptor; H2R: Histamine H2 receptor; H3R: Histamine H3 receptor; H4R: Histamine H4 receptor; HDC: Histidine decarboxylase; IBD: Inflammatory bowel disease; IBS: Irritable bowel syndrome; RT-PCR: Reverse transcription-polymerase chain reaction; TNBS: Trinitrobenzene sulphonic acid; VEGF: Vascular endothelial growth factor
Key Words Histamine, Histamine H4 receptors, Gastrointestinal tract
Send correspondence to: Gabriella Coruzzi, Department of Human Anatomy, Pharmacology and Forensic Medicine, Section of Pharmacology, University of Parma, Via Volturno 39, 43100 Parma Italy, Tel: 0039-0521-903851, Fax, 0039-0521-903852, E-mail:gabriella.coruzzi@unipr.it