Open access

Capsaicin-Sensitive Afferentation Represents a New Mucosal Defensive Neural Pathway System in the Gastric Mucosa in Patients with Chronic Gastritis

Written By

Jozsef Czimmer, Imre Laszló Szabo, Janos Szolcsanyi and Gyula Mozsik

Submitted: August 29th, 2012 Published: January 16th, 2013

DOI: 10.5772/52883

Chapter metrics overview

1,957 Chapter Downloads

View Full Metrics

1. Introduction

The name of capsaicin is generally used in the medical research, however this material does not contain a uniform chemical entity. Capsaicinoids covers 5 analogues and 2 homologues components (Mozsik et al. 2009) (Fig. 1).

It has been established that capsaicinoids interact with capsainin-sensitive afferent nerves representing a novel regulatory pathway of gastrointestinal funcions (Jancsó et al. 1967, 1968, 1970). Capsaicin-sensitive afferent nerves contain a temperature-gated ion channel called capsaicin receptor or transient receptor potencil vanilloid 1 (TRPV1) which is expressed by a subgroup of primary afferent nociceptive neurons (Szolcsanyi, 2004). The capsaicin receptor has been cloned (Caterina et al., 1997) and has been found to be linked to a cation channel. It is gated by capsaicin and other capsaicinoids (some vanilloids) by various treatments including low pH, noxius heat and various pain-producing endogenous an exogenous chemicals. Thus, those sensory nerve endings possessing these ion channels are susceptible to being stimulated in the gastric mucosa. Upon stimulation with capsaicin, these afferent fibers develop four response stages (excitation, sensory-blocking, long-term selective neurotoxic impairment, and irreversible cell destruction), depending on the dose and duration of exposure of the component (Mózsik et al. 2001). A low dose of capsaicin (nanograms to micrograms per kilogram) causes excitation of the nerve endings, and neuropeptides (substance P [SP], calcitonin gene-related peptide [CGRP], and somatostatin) are released (Holzer et al. 1998, 1999) (Szolcsányi 2004). These mediators can increase mucosal blood flow by vasodilatation (Holzer et al. 1991), can activate mast cells and immunocells in the mucosa (Stead 1992), and are involved in drug effects (Mózsik et al. 2004, 2005), and somatostatin can elicit systemic anti-inflammatory and analgetic “sensory functions.” The immunodistribution of neuropeptides (SP, VIP, NPY, SOM, GAL, and TH) released from the sensory neurons and their neuroimmune function are known in H. pylori-positive gastritis (Sipos et al. 2006). Notwithstanding studies supported that this gastric mucosal protective mechanism provided by capsaicin-sensitive afferent nerves exists in patients with chronic gastritis, and its extent does not depend on the presence or absence of H. pylori infection. In other words, the gastric mucosal protection produced by capsaicin-sensitive afferent nerves is one of the general defense mechanisms against the different noxious agents that induce chronic gastritis (Dömötör et al. 2006).

Figure 1.

Names and chemical structures of capsaicin homologs and analogs (with knowledge and allowance of Mozsik et al. 2009).

The vagal nerve has a key-role in the development of gastrointestinal mucosal damage and prevention (Mozsik et al., 1982). The key-role of vagal nerve has been emphasized dominantly in the aggressive processes to gastrointestinal (GI) mucosa (such as in peptic ulcer disease, gastric mucosal damage, etc.) as evidenced from GI investigations in animal models and as well as in human clinical practice. The application of capsaicin in the animal experimentswas used as a specific tool to investigate those primary afferent nociceptive neurones (Szolcsanyi, 2004; Buck and Burks, 1986; Holzer, 1988; 1991; Szállasi and Blumberg, 1999) involved in the different physiological, pathological processes.

Szolcsanyi and Bartho (1981) were the first authors, who clearly identified the beneficial and harmful effect of capsaicin in experimental peptic ulcer in rats, following varying doses of capsaicin. Later, Holzer undertook extensive investigations on the mode of action of capsaicin on GI functions (Holzer, 1998; 1999; Buck and Burks, 1986; Szállasi and Blumberg, 1999). We also contributed during the 1980’s to GI capsaicin research from studies in animal models (Mózsik et al., 1997c). Recently the new drug, lafutidine, was introduced in the medical treatment of GI mucosal damage (Ajioka et al., 2000; 2002; Onodera et al., 1995; 1999; Takeuchi, 2006). Lafutidine is a histamine histamine type 2 receptor (H2R) blocking compound which uniquely has typical capsaicin actions on the target organ.

Capsaicin-sensitive vagal neural afferentation is one of the defensive mechanisms. These nerves have been shown to play a role in gastric mucosal protection by preventing drug -induced mucosal injury in animals (Abdel-Salam et al. 1999; Mózsik et al. 1997a; Reinshagen at al. 1996) and by decreasing the amount of indomethacin (IND)-induced gastric microbleeding in healthy human subjects (Kang JY et al. 1995; Mózsik et al. 2004b; Mózsik et al. 2005). These mechanisms are well known to be important in protection against gastritis caused by various harmful effects. The TRVP 1 receptors were also detected in the area postrema and in the nucleus tractus solitary, where the afferent fibres of the vagus nerve taper, and have key role in regulation of gastric functions i.e. secretion, motiity and protestion mechanisms.

The vagus nerve consists of 10% efferent nerves, 90% afferents. About 10% of these afferent nerves are capsaicin-sensitive. The amount of efferent nerves and the capsaicin-sensitive afferent nerves is roughly equal in the vagus nerve. Capsaicin exposure exerts various responses in these afferent nerves depending on dose and exposure duration (excitation, sensory-blocking, long-term selective neurotoxic impairment and irreversible cell destruction) (Vincze et al. 2004). During exposure to small doses of capsaicin (from ng/kg to μg/kg body weight) neurotransmitters, such as: substance P (SP), calcitonin gene-related peptide (CGRP) and somatostatin, are released from the nerve endings (Caterina et al. 1997; Mózsik et al. 2001; Holzer 1998). These mediators are responsible for increasing mucosal blood flow by vasodilatation (Holzer 1999), activation of mast cells and other immune cells in the mucosa (Szolcsányi 2004; Holzer et al. 1991) and defense of gastrointestinal mucosa.

Capsaicin has been used in human studies, looks to be a suitable treatment tool in several fields of medicine that can be seen from several running and completes multicentric controlled studies worldwide. The United States Pharmacopeia (USP) describes the list of capsaicins and their definition, identification, melting range, and content of capsaicin, dihydrocapsaicin and other capsaicinoids as follows (USP30-NF25. 2006 Edition, pp.1609): capsaicin contains not less than 90.0 % and more than 110.0 % of the labelled percentage of total capsaicinoids. The content of capsaicin is not less than 55 %, and the sum of the contents of capsaicin and dihydrocapsaicin should not be less than 75 %. The content of other capsaicinoids should not be more than 15 %, all calculated on the dried basis. The circumstances of plant cultivation, preparation, storage and other facts are summarized in the drug master file (DMF). The DMF of capsaicin originated from India was signed by Food and Drug Administration (FDA) in the United States as existing registration, which allows the usage of capsaicin as basic source for capsaicin-containing drugs. This type of capsaicinoids (briefly capsaicin) was used in our previous studies (Mozsik et al. 2009a, 2009b, 2011).

Gastritis is a pathomorphological appearance of inflammation in the gastric mucosa. Acute and chronic gastritis can be differentiated on the basis of the development and process of the disease. Chronic gastritis may be caused by different factors such as Helicobacter pylori infection, bacterial overgrowt in a hypochlorhydric stomach, autoimmune mechanisms, or chemical agents such as long-term nonsteroidal anti-inflammatory drug (NSAID) treatment, and bile reflux (Owen 2003; Appelman 1994, Szabo et al. 2012), for details about mechanisms we refere to the other chapters of this book. Nowdays, the importance of Helicobacter pylori infection is increasing as the main causative factor in gastric diseases in humans. This bacterium is highly prevalent in many countries (Parsonnet 1995) and it increases the risk for development of gastric and duodenal ulcer disease, gastric cancer, and gastric mucosa-associated lymphoid tissue lymphoma (Janulaityte-Gunther et al. 2005; Mitani et al. 2004; Peng et al. 1998; Salih et al. 2005; Zhang et al. 2005a, 2005b). Dysfunction of gastrointestinal mucosal defense mechanisms is also involved in the development of gastric diseases. Capsaicin-sensitive afferent nerves take part in gastric mucosal protection in animals (Mózsik et al. 1997a; Reinshagen et al 1996) and in healthy human subjects (Kang et al. 1995; Mózsik et al. 2004a, 2005a), and the presence of these fibers is proved to play a role in the development of human gastrointestinal disorders including gastritis, peptic ulcer, polyp without and with dysplasia, tumor, and inflammatory bowel diseases (Dömötör et al. 2005; Vincze et al. 2004). The immunodistribution of neuropeptides (SP, VIP, NPY, SOM, GAL, and TH) released from the sensory neurons and their neuroimmune function are known in H. pylori-positive gastritis (Sipos et al. 2006).

Advertisement

2. Recent results in human studies

Presentation of capsaicin-sensitive afferentation in the H. pylori positive and H. pylori negative chronic gastritis in patients has been studied by Mózsik et al. (2011): The symptoms of patients sufferring from chronic gastritis with or without H. pylori infection (H. pylori positive, n=21, age 39-68 years, screened with [14C] urea breath test, rapid urease test, Warthin-Starry silver staining and specific histological examinations; H. pylori negative, n=30, age 39-68 years) were nonspecific including gastric dyscomfort sensation, nausea, loss of apetite and vomiting. The gastric tissue samples from the stomach and antrum were examined by an independent histopathologist and classified of chronic gastritis according to the Sydney’s System (Price et al. 1991). The immunohistological studies were carried out on formalin fixed, parafin embedded tissue samples of gastric mucosa using the peroxidase-labeled polymer method (Lab Vision Co., Fremont, USA). SP was detected by the NC1/34HL rat monoclonal antibody, the TRPV1 receptor and CGRP were labeled using polyclonal rabbit antisera (all from Alcam Ltd., UK, Cambridge) (Dömötör et al. 2006) (Figs. 2-4).

Figure 2.

Immunohistochemical distribution of capsaicin receptor (transitoric receptor potential vanilloid) (TRPV1 in the gastric mucosa of a healthy (A) and of patient with H. pylori negative (B) and H. pylori positive (C) chronic gastritis. Arrows indicate the immunosigns in the epithelial layer of the gastric mucosa (original magnification: 100x). From the ref. (Mózsik et al. 2011), with permission.

Figure 3.

Immunoshistochemical distribution of calcitonin gene-related peptide (CGRP) in the gastric mucosa of healthy subject (A), of patient with H. pylori negative (B) and H. pylori positive (C) chronic gastritis. Arrows demosntrate the immunosign in the epithelial layer of the gastric mucosa (original magnification: 100x). From the ref. (Mózsik et al. 2011), with permission.

Figure 4.

Immonohsitochemical distribution of subastane P (SP) in gastric mucosa of healthy subject (A), of pateints with H. pylori negative (B) and positive (C) chronic gastritis. Arrows show the immunosigns in the epithelial layer of the gastric mucosa (original magnification: 100x). From the Ref. (Mózsik et al 2011), with permission.

Presentation of capsaicin-sensitive afferention of vagal nerve in patients with H. pylori positve chronic gastritis of patients, before after after eradication treatment (Mózsik et al 2011):Very recently the same clinical and immunohistochemical examinations were carried out as those mentioned above in patients with H. pylori positive chronic gastritis before and after eradication treatment. These observations were carried out in 38 persons, including 20 healthy subjects and 18 patients with H. pylori positive gastritis. The age of persons with histologically intact gastric mucosa (controls) were between 41 and 67 years (mean=52.2 years). The age of patients (6 males, 12 females) was 39 to 68 years (mean = 56.4 years).

The time period between the first and control gastroscopy was 6 weeks. The biopsies were taken from the corpus and antrum of patients with chronic gastritis, before and after eradidation treatment, and from healthy persons. H. pylori positive patients underwent 7 days eradication treatment with combination of double dose PPI (pantoprazole 2x40 mg/day), amoxicillin (1000 mg twice daily) and clarithromycin (500 mg twice daily) according to current European guidelines (Malferteiner et al. 2007). After this one week combination treatment, patients continued to take normal dose of PPI for another week. The H. pylori infection was detected before and after by [14 C] urea breath test, rapid urease test, Warthing-Starry silver staining and specific histological and immmunohistological examinations. The results of eradication treatment was succesfull in 89%, the gastric histology indicated normal picture in 22% of cases, and in 78 per cent patient the mucosa showed moderate gastritis (Lakner et al. 2011).

Expression of TRPV1 receptor, CGRP and SP in the gastric mucosa of patients with H. pylori negative and positive chronic gastritis, and before and after successful eradication treatment (Mózsik et al 2011): The expression of TRPV1 and CGRP increased in the gastric mucosa of patients with chronic gastritis, however, it was an unexpected that the increase expresson of TRPV1 and CGRP did not depend on the presence of H. pylori infection. The changes in expression of SP were not significant between these groups of patients.

Another surprising result was obtained in patients with H. pylori positive chronic gastritis before and after sucessfull eradication treatment. The extent of expression of TRPV1, CGRP remained at the same level after eradication. No significant changes were obtained in the expression of SP in the gastric mucosa in these patients (Fig. 4) (Mózsik et al 2011).

Figure 5.

Chamges in the expression of capsaicin receptor (TRPV1), calcitonin gene-ralated peptide (CGRP) and substabtance P (SP) in the human gastric mucosa of healthy voluntaries(histologically intact) (A), H. pylori positive (B), H. pylori negative (C) and H. pylori positive before (D) and after eradication (pantoprazole 40, amoxicillin 1000 and clarithromycin 500 mg, all two times per day, for seven days) (n=number of patients) (Mózsik et al 2012).

These findings suggest potential role of capsaicin-sensitive afferent vagal nerve in the development of chronic gastritis and the eradication treatment (Mózsik et al 2011): From the experimental observations it could be concluded that actions of capsaicin are dose-dependent (Mozsik et al. 2001, 2005a, 2009b). The types of gastric mucosal injuries could be prevented by application of small doses (200 to 800µg/person) of capsaicin (Mózsik et al. 2001). Results of these observations suggest mucosal protecting effect of capsaicin (acting via the stimulation of capsaicin-sensitive afferent fibres of vagal nerve) in healthy human subjects. These observations showed that the expression of TRPV1 and CGRP increased siginicantly in inflamated chronic gastritis, and no significant change was obtained in SP levels. However, these immunohistochemical results did not differ in patients with H. pylori positive and negative chronic gastritis. Capsaicin-sensitive afferention did not differ before and after (6 weeks) successfull eradication treatment in patients with chronic H. pylori positive gastritis (meanwhile the control biopsy was normal in 22% and in 78% indicated in moderated histological picture of gastritis) (Lakner et al. 2011).

Explantaion of study group of the for the unchanged immunohistochemical distribution of TRPV1, CGRP and SP of gastric H. pylori positive chronic gastritis before vs. after eradication treatment were as follows (Mozsik et al. 2011):

  1. Six week time period (including the eradication treatment) is not enough time for the complete healing of chronic gastritis.

  2. The six-week time period (after eradication treatment) is probably not enought time for complete histologically recovery of chronic H. pylori positive infection in patients in term of histology and immunohistology.

  3. The H. pylori bacteria as etiological factors might represent only one of the factors causing chronic gastritis (in term of histology);

  4. The immunohistological distribution (expression rate) of TRPV1, CGRP and SP are independent ont the chronic gastritis produced by different physical, chemical, bacterological or immunological agents. However, the increased expression of TRPV1, CGRP is involved in the gastric mucosal damage and the normalization of these changes can be obtained by other way as the classical eradication treatment (Lakner et al. 2011).

Kozlowski et al. (2011) conluded from their study on chronic gastritis: 1. Chronic supeficial gastritis coexists with significantly higher proliferative activity of gastric mucosal glandular epithelium, particulary in relation to the prepyloric area and 2. Changes of proliferative activity of gastric mucosal glandular epithelium are independent of age, histotopography and of H. pylori colonization.

Recent investigations showed that the expression of TRPV1 and CGRP increased significantly inthe epithelial layer of the gastric mucosa in patients with H. pylori - positive and -negative chronic gastritis. The significant etiological role of H. pylori in the development of chronic gastritis has received great attention in the pertinent literature; for this reason, we compared the differences in TRPV1,CGRP, and SP expression in H. pylori positive or -negative chronic gastritis, suggesting their etiological role in the development of chronic gastritis. No significant differences were obtained between H. pylori-positive and H. pylori-negative patients, but values of both groups with chronic gastritis differed significantly from those of histological intact mucosa of healthy human subjects. Results also indicated that chronic gastric inflammation is one of the general tissue reactions to different noxious agents, and H. pylori is only one of these in patients. It must be emphasized that clinicians are able to specifically demonstrate the presence of H. pylori (by UBT, rapid urease test, and specific histological staining), however, we have no specific methods for well demonstration of other (suggested) etiological factors.

In animal experiments, different noxious agents produce the same (or basically similar) pathological, biochemical (oxygen free radicals), etc., events in the development of gastrointestinal mucosal injury and its prevention (Mózsik et al. 1992). Gastric mucosal damage can be produced by direct application of ethanol and indomethacin and it can be dose dependently prevented by the topical application of capsaicin in healthy volunteers (Mózsik et al., 2005a). Endogenous (increased production of gastric HCl in 4-hr pylorus-ligated rats) and exogenous (indomethacin given s.c. in a 4-hr experiment, without pylorus ligation) factors produced changes in functional status and damaged the gastric mucosa in rats. The immunohistochemical distribution of TRPV1, CGRP, and SP decreased significantly during this time; the levels of TRPV1 and CGRP returned to those of healthy controls dose dependently by application of omeprazole and omeprazole-like compounds, and no significant change was detected in the immunodistribution of SP (Mózsik et al. 1997b). There is no real explanation for the different expression rates of TRPV1 and mediators released from the sensory nerves. Similar differences in TRPV1, CGRP, and SP have been observed in many other conditions (in acute animal models and in patients with chronic gastrointestinal disorders). The following explanations have been suggested for these differences in expression of TRPV1 and mediators released from sensory nerves (Dömötör et al., 2007): (1) the regulation of SP differs from that of TRPV1 and CGRP regarding the development of chronic gastritis and (2) the sensitivity of SP regulation is lower than in the cases of TRPV1 and CGRP. The increased level of TRPV1 and CGRP is accepted as a signal of an increased defense mechanism produced by capsaicin-sensitive afferent nerves in animal experiments (Mózsik et al. 2005a), and the topical application of capsaicin dose-dependently prevented the mucosal injury produced by intragastrically applied ethanol and indomethacin in healthy human subjects (Mózsik et al. 2005b). These findings suggest that increased expression of TRPV1 and CGRP is associated with increased gastric mucosal protection. This gastric mucosal protective mechanism provided by capsaicin-sensitive afferent nerves exists in patients with chronic gastritis, and its extent does not depend on the presence or absence of H. pylori infection. In other words, the gastric mucosal protection produced by capsaicin-sensitive afferent nerves is one of the general defensive mechanisms against the different noxious agents that induce chronic gastritis.

Advertisement

3. Conclusions

The results of above mentioned animal and human observations indicated clearly the following considerations:

1. Both acute and chronic gastritis can be induced by different reasons, like chemicals (drugs) or bacteria (most emphysized one H. Pylori). Both H. pylori positive and negative gastritis can be acute or chroinic. In case of patients with H.plyori negative gastritis, the therapeutic approach follows the traditional medical treatment, while H.pylori positive patients with gastritis are suggested a rational eradtication treatment only (accepted by many international consensus meetings).

Mózsik et al. and Lakner et al. (2011) have demonstrated that while chronic H. pylori pozitive gastritis heals entirely after a sucessful eradication therapy (which represents an important step to prevent development of gastric cancer), the extents of TRVP1, CGRP remained in increased level (in comparison to the normal gastric mucosa). This indicates that there is at least one other important defensive mechanism than antibiotic eradiction treatment, the capsaicin-sensivite afferention of vagal nerve (results clearly indicated that independent from H. pylori status and independent from eradication).

Generally it can be concluded that: 1. there can be different mucosal defensive mechanisms playing key role in treatment of H. plyori positive chronic gastritis: a. eradication treatment and b. stimulation of capsaicin sensitive afferentation; 2. eradication treatment is independent from capsaicin-sensitive afferention (defensive) mechanism; 3. it should be considered to amend treatment protocols of H. pylori positive chronic gastritis (conventional eradication therapy and success control) with modification of functional state of capsaicin-sensitive afferentation. Medical effect of capsaicin for modification of capsacin-sensitive afferent nerves depends on its dosages, more clinical findngs are needed in the field, that observations are in progress (Mozsik et al. 2009b, 2011).

Advertisement

Acknowledgments

This chapter was supported by MEDICZIM Kft, Hungary and ALAPITVANY AZ EGESZSEG UGYEBEN DOLGOZOKERT, Hungary.

References

  1. 1. Abdel-SalamO. M. E.DebreceniA.MózsikGy.1999Capsaicinsensitive afferent sensory nerves in modulating gastric mucosal defense against noxious agents. J Physiol Paris 93443454
  2. 2. AijokaH.MiyakeH.MatsuuraN.2000Effect of FRG-8813, a new-type histamine H2-receptor antagonist, on the recurrence of gastric ulcer healing by drug treatment. Pharmacology. 618390
  3. 3. AijokaH.MatsuuraN.MiyakeH.2002High quality of ulcer healing in rats by lafutidine and new-tipe histamine H2-receptor antagonist: involvement of capsaicin of sensitive sensory neurons. Inflammopharmacology 10483493
  4. 4. Appelman HD1994Gastritis: terminology, etiology, and clinicopathological correlations: another biased view.Hum Pathol 2510061019
  5. 5. Buck SH, Burks TF.1986The Neuropharmacology of capsaicin: review of some recent observation.Pharmacol Rev. 38179226
  6. 6. MJCaterinaChumacher.MATominagaM.RosenT. A.JDLevineJulius. D.1997The capsaicin receptor: a heat-activated ion channel in the pain pathway.Nature389816824
  7. 7. DixonM. F.GentaR. M.YardleyJ. H.CorreaP.1996Classification and grading of gastritis: the updated Sydney systemAm J Surg Pathol 2011611181
  8. 8. DömötörA.PeidlZs.VinczeÁ.HunyadyB.SzolcsányiJ.KereskayL.SzekeresGy.MózsikGy.2005Immunohistochemical distribution of vanilloid receptor (TRPV1), calcitonin generelated peptide (CGRP) and substance-P (SP) in the gastrointestinal mucosa of patients with different gastrointestinal disorders. Inflammopharmacology 13161177
  9. 9. DömötörA.KereskayL.SzekeresGy.HunyadyB.SzolcsányiJ.MózsikGy.2006Participation of capsaicin sensitive afferent nerves in the gastric mucosa of patients with helicobacter pyloripositive or-negative chronic gastritis. Dig Dis Sci. 52411417
  10. 10. HolzerP.LippeI. T.1988Stimulation of afferent nerve endings by intragastric capsaicin protects against ethanol-induced damage of gastric mucosa.Neuroscience279817
  11. 11. HolzerP.LivingstonE. H.SariaA.GuthP. H.1991Sensory neurons mediate protective vasodilatation in rat gastric mucosa.Am J Physiol 260363370
  12. 12. HolzerP.Afferent nerve-mediated control of gastric mucosal blood flow and protection.In: Costa M, Surrenti C, Gorini S, Maggi CA, Meli A, Eds. Sensory nerve and neuropeptides in gastroenterology. From basic science to clinical perspective. New York: Plenum Press; 199197108
  13. 13. HolzerP.1998Neural emergency system in the stomach.Gastroenterology114823830
  14. 14. HolzerP.1999Capsaicin cellular targets, mechanisms of action and selectivity for thin sensory neurons. Pharmacol Rev 43143201
  15. 15. JancsóN.Jancsó-GáborA.SzolcsányiJ.1967Direct evidence for neurogenic inflammation and its prevention by denervation and by pretreatment with capsaicin.Br J Pharmacol 3113851
  16. 16. JancsóN.Jancsó-GáborA.SzolcsányiJ.1968The role of sensory nerves endings in the neurogen inflammation induced in human skin and in the eye and paw of the rat. Br J Pharmacol 333241
  17. 17. Jancsó-GáborA.SzolcsányiJ.JancsóN.1970Irreversible impairment of the irregulation induced by capsaicin and similar pungent substances in rat and guinea-pigs. J Physiol (London). 206495507
  18. 18. Janulaityte-GuntherD.KucinskieneR.KupcinskasL.PavilonisA.LabanauskasL.CizauskasA.SchmidtU.WadstromT.AndersenL. P.2005The humoral immune response to Helicobacter pylori infection in children with gastrointestinal symptoms. FEMS Immunol Med Microbiol 44205212
  19. 19. KangJ. Y.YeohK. G.ChiaH. P.LeeH. P.ChiaY. W.GuanR.YapI.1995Chili-Protective factor against peptic ulcer? Dig Dis Sci 40576579
  20. 20. KozlowskiW.JochymskiC.MarkiewioczT.Chronicgastritis.InTonino. P.EdGastritis and Gastric Cancer- New Insights in Gastroportection, Diagnosis and Treatment. Publisher by inTech, Rijeka, Croatia. 20117592
  21. 21. LaknerL.DömötörA.TóthCs.SzaboI. L.MeckerÁ.HajósR.KereskaiL.SzekeresGy.DöbrönteZ.MózsikGy.2011Capsaicin-sensitive afferentation represents an indifferent defensive patway from eradication in patients with H.pylori positve gastritis. World J Gastrointest Pharmacol Ther 23641
  22. 22. MalfertheinerP.MegraudF.O’MorainC.BazzoliF.El -OmarE.GrahamD.HuntR.RokkasT.VakielN.KuipersE. J.Current concepts in the management of Helicobacter pylori infection. The Maastricht III. Consensus Report. Gut 20075677281
  23. 23. MitaniK.TatsutaM.IishiH.YanoH.UedoN.IsekiK.NaraharaH.2004Helicobacter pylori infection as a risk factor for gastric ulceration. Hepato-Gastroenterology 51309312
  24. 24. MózsikGy.MoronF.JávorT.1982Cellular mechanisms of the development of gastric mucosal damage and of gastroprotection induced by prostacyclin in rats. A pharmacological study, Prostagland. Leukot. Med. 97184
  25. 25. MózsikGy.KirályÁ.SütőG.VinczeÁ.1992ATP breakdown in the development of gastrointestinal mucosal damage and its prevention in animals and human (An overview of 25 years ulcer research studies). Acta Physiol Hung 803980
  26. 26. MózsikGy.NagyL.KirályÁ.1997aEds. Twenty-five Years of Peptic Ulcer Research in Hungary. from Basic Science to Clinical Practice 1971-1995. Budapest: Akademiai Kiadó; 1448
  27. 27. MózsikGy.NagyL.PárA.Rainsford1997bEds. Cell Injury and Protection in the Gastrointestinal Tract: from Basic Science to Clinical Perspectives. Dordrecht: Kluwer Academic Publisher.
  28. 28. MózsikGy.Abdel-SalamO. M. E.SzolcsányiJ.1997cCapsaicin-Sensitive Afferent Nerves in Gastric Mucosal Damage and ProtectionBudapest: Akadémiai Kiadó; 1997c.
  29. 29. MózsikGy.VinczeÁ.SzolcsányiJ.2001Four response stages of capsaicin-sensitive primary afferent neurons to capsaicin and its analog: gastric acid secretion, gastric mucosal damage and protection.J Gastroenterol Hepatol 1610931097
  30. 30. MózsikGy.BelágyiJ.SzolcsányiJ.PárG.PárA.RumiGy.RáczI.2004aCapsaicin-sensitive afferent nerves and gastric mucosal protection in the human healthy subjects. A critical overview. In: Takeuchi K, Mózsik Gy (Eds) Mediators in Gastrointestinal Protection and Repair. Research Signpost, Kerala, 4362
  31. 31. MózsikGy.PárA.PárG.JuricskayI.FiglerM.SzolcsányiJ.2004b Insight into the molecular pharmacology to drugs acting on the afferent and efferent fibers of the vagal nerve in the gastric mucosal protection. In: Sikiric P, Seiwerth P, Mózsik Gy, Arakawa T, Takeuchi K (Eds) Ulcer Research. Proceedings of the 11th International Conference. Monduzzi, Bologna, 163168
  32. 32. Mózsik Gy, Peidl Zs, Szolcsányi J, Dömötör A, Hideg K, Szekeres Gy, Karádi O, Hunyady B (2005a). Participation of vanilloid/ capsaicin receptors, calcitonin gene-related peptide and substance P in gastric protection of omeprazole and omeprazole-like compounds. Inflammopharmacology 13:139–159.
  33. 33. Mózsik Gy., Rácz I., Szolcsányi J. (2005b). Gastroprotection induced by capsaicin in human healthy subjects. World J Gastroenterol 11:5180–5184.
  34. 34. MózsikGy.DömötörA.PastT.VasV.PerjésiP.KuzmaM.BlazicsGy.SzolcsányiJ.2009aCapsaicinoids: From the Plant Cultivation to the Production of the Human Medical Drug.Akadémiai Kiadó, Budapest
  35. 35. MózsikGy.PastT.Abdel-SalamO. M. E.KuzmaM.PerjésiP.2009bInterdisciplinary review for correlation between the plant origin capsaicinoids, non-steroidal antiinflammatory drugs, gastrointestinal mucosal damage and prevention in animals and human beingsInflammopharmacology17113150
  36. 36. MózsikGy.PastT.DömötörA.KuzmaM.PerjésiP.2010Production oforally applicable new drug or drug combinations from natural origin capsaicinoids for human medical therapy. Curr Pharm Des 1611971208
  37. 37. MózsikGy.SzabóI. L.DömötörA.2011Approach to role of capsaicin-sensitive afferent nerves in the development and healing in patients with chronic gastritis.In: Tonino P (ed). Gastritis and New Gastric Cancer- New Insights in Gastroprotection, Diagnosis and Treatments. 2011 Publisher by in Tech. Rijeka, Croatia 2011. 2546
  38. 38. MózsikGy.SzabóI. L.CzimmerJ.2012Vulnerable points of the Helicobacter pylori story- based on animal and human observations (1975-2012). Buzás G (Ed.): Helicobacter pylori: 2012. Bentham Science Publishers (in press).
  39. 39. OnoderaS.ShibataM.Tanakaet.al1999Gastroprotective mechanisms of lafutidine, a novel anti-ulcer drug with histamine H2-receptor antagonist activity,Artneim Forsch. Drug Res. 4951926
  40. 40. Owen DAMB2003Gastritis and carditis.Mod Pathol 16325341
  41. 41. ParsonnetJ.1995The incidence of Helicobacter pylori infection.Aliment Pharmacol Ther 24551
  42. 42. PengH.RanaldiR.DissT. C.IsaacsonP. G.BearziI.PanL.1998High frequency of CagA+ Helicobacter pylori infection in high-grade gastric MALT B-cell lymphomas.J Pathol 185409412
  43. 43. Price AB, Misiewicz JJ.1991Sydney classification for gastritis.Lancet174 EOF
  44. 44. ReinshagenM.PatelA.SottiliM.FrenchS.SterniniC.EysseleinV. E.1996Action of sensory neurons in an experimental rat colitis model of injury and repairAm J Physiol 2707986
  45. 45. BASalihAbasiyanik. M. F.SaribasakH.HutenO.SanderE.2005A follow-up study on the effect of Helicobacter pylori radication on the severity of gastric histology. Dig Dis Sci 5015171522
  46. 46. SiposG.AltdorferK.PongorE.ChenL. P.FehérE.2006Neuroimmune link in the mucosa of chronic gastritis with Helicobacter pylori infectionDig Dis Sci. 2006; 5118107
  47. 47. Stead RH1992Innervation of mucosal immune cells in the gastrointestinal tract.Reg Immunol 49199
  48. 48. SzabóI. L.CsekoK.CzimmerJ.MózsikGy.2012Diagnosis of Gastritis- Review from Early Pathological Evaluation to Present Day Management. In: Mózsik Gy (Ed). "Gastritis" Publisher by In Tech. Rijeka, Croatia (in press).
  49. 49. SzállasiA.BlumbergM.1999Vanilloid (capsaicin) receptors and mechanisms.Pharmacol Rev. 51159211
  50. 50. SzolcsányiJ.BarthóL.1981Impaired defense mechanisms to peptic ulcer in the capsaicin-desensitized rat. In: Mózsik Gy, Hanninen O, Jávor T, Eds. Advances in Physiological Sciences, 29Gastrointestinal Defense Mechanisms. Oxford and Budapest: Pergamon Press and Akadémiai Kiadó; 3951
  51. 51. SzolcsányiJ.2004Forty years in capsaicin research for sensory pharmacology and physiology.Neuropeptide. 3837784
  52. 52. TakeuchiK.2006Unique profile of lafutidine: a novel histamine H2receptor antagonist: mucosal protection throughout GI mucosal mediated by capsaicin-sensitive afferent nerves. Acta Pharmacol Sinica Suppl. 27-35.
  53. 53. VinczeÁ.SzekeresGy.KirályÁ.BódisB.MózsikGy.2004The immunohistochemical distribution of capsaicin receptor, CGRP and SP in the human gastric mucosa in patients with different gastric disorders. In: Sikiric P, Seiwerth S, Mózsik Gy, Arakawa T, Takeuchi K (Eds) Ulcer Research. Proceedings of 11th International Congress of Ulcer Research. Monduzzi, Bologna, 149153
  54. 54. ZhangC.YamadaN.WuY. L.WenM.MatsuhisaT.MatsukuraN.2005aComparison of Helicobacter pylori infection and gastric mucosal histological features of gastric ulcer patients with chronic gastritis patients.World J Gastroenterol 11976981
  55. 55. ZhangC.YamadaN.WuY. L.WenM.MatsuhisaT.MatsukuraN.2005bHelicobacter pylori infection, glandular atrophy and intestinal metaplasia in superficial gastritis, gastric erosion, erosive gastritis, gastric ulcer and early gastric cancer. World J Gastroenterol 11791796

Written By

Jozsef Czimmer, Imre Laszló Szabo, Janos Szolcsanyi and Gyula Mozsik

Submitted: August 29th, 2012 Published: January 16th, 2013