The Role of Visceral Hypersensitivity in Irritable Bowel Syndrome: Pharmacological Targets and Novel Treatments

Irritable bowel syndrome (IBS) is the most common disorder referred to gastroenterologists and is characterized by altered bowel habits, abdominal pain, and bloating. Visceral hypersensitivity (VH) is a multifactorial process that may occur within the peripheral or central nervous systems and plays a principal role in the etiology of IBS symptoms. The pharmacological studies on selective drugs based on targeting specific ligands can provide novel therapies for modulation of persistent visceral hyperalgesia. The current paper reviews the cellular and molecular mechanisms underlying therapeutic targeting for providing future drugs to protect or treat visceroperception and pain sensitization in IBS patients. There are a wide range of mediators and receptors participating in visceral pain perception amongst which substances targeting afferent receptors are attractive sources of novel drugs. Novel therapeutic targets for the management of VH include compounds which alter gut-brain pathways and local neuroimmune pathways. Molecular mediators and receptors participating in pain perception and visceroperception include histamine-1 receptors, serotonin (5-hydrodytryptamine) receptors, transient receptor potential vanilloid type I, tachykinins ligands, opioid receptors, voltage-gated channels, tyrosine receptor kinase receptors, protease-activated receptors, adrenergic system ligands, cannabinoid receptors, sex hormones, and glutamate receptors which are discussed in the current review. Moreover, several plant-derived natural compounds with potential to alleviate VH in IBS have been highlighted. VH has an important role in the pathology and severity of complications in IBS. Therefore, managing VH can remarkably modulate the symptoms of IBS. More preclinical and clinical investigations are needed to provide efficacious and targeted medicines for the management of VH.

Expression of Substance P in the Experimental Diabetic Rat Retina / 대한해부학회지

Substance P (Sub P) being composed of 11 amino acids sequence is a kind of tachykinin family peptides. It has been known that this substance plays a role of neurotransmitter and/or neuromodulator and is a very potent vascular growth factor in the nervous system. This study has been investigated expression pattern of Sub P in the rat retina at normal and alteration of Sub P expression following diabetic injury using immunohistochemistry. Diabetic condition was induced by a single injection of streptozotocin in Sprague-Dawley rats aged 8 weeks. The animals showing high blood glucose levels (above 300 mg/dL) were cared for 1, 4, 8 and 12 weeks, respectively. The whole-mounted or sectional preparations of the retinas were used for Sub P immunohistochemistry. Sub P immunoreactivity has been localized in subsets of amacrine cells in the inner nuclear layer (INL) and displaced amacrine cells in the ganglion cell layer (GCL) in the normal retina. The dendrites from amacrine cells in the INL were ramified with strata 1 and 3, and those from displaced amacrine cells in the GCL with strata 5 of the inner plexiform layer. Sub P immunoreactive neurons in both the INL and the GCL were more densely populated in the superior half of the retina. During diabetes, the cell number of Sub P immunoreactive neurons was decreased to one third of the normal value at 4 weeks of diabetes and then slightly increased to half of the normal value at 12 weeks of diabetes. In addition, Sub P mRNA levels were reduced at 4 weeks but reincreased at 12 weeks. These results suggest that Sub P in the rat retina at normal state may function differentially in the superior or the inferior halves and Sub P synthetic pathway in the retinal neurons maybe irradiated in earlier stages of diabetic retinopathy.

Immunohistochemical demonstration of opioids and tachykinins in human pineal gland.

The human pineal gland secretes melatonin in a circadian rhythm manner. The rhythm of melatonin synthesis is primarily controlled by the noradrenergic sympathetic system originating from the superior cervical ganglion. Several neurotransmitters/neuropeptides have been reported to influence the production of melatonin in the pineal glands of many mammalian species. Both opioid peptide, a pain suppressing peptide and substance P, a pain inducing peptide were also reported to be present in the pineal gland of several kinds of mammals. However, few studies have been demonstrated in humans. Therefore, in the present study, the immunohistochemical investigation was performed in the human pineal gland by using antisera raised against leu-enkephalin, met-enkephalin and beta-endorphin to demonstrate an opioidergic system; and antisera raised against substance P, neurokinin A, and neurokinin B to study a tachykinin system. A high amount of leu- and met-enkephalin immunoreactivities were observed in intrapineal neuronal-like cells while very few were presented in nerve fibers. This result suggests a local regulatory function or paracrine opioidergic control in human pineal. Substance P- and neurokinin A-immunoreactivities, but not neurokinin B were observed in the human pineal gland. They are located mostly in nerve fibers but a few in neuronal-like cells. The tachykininergic control of human pineal is mainly from the nerve fibers which have their perikaryal origin outside the gland. Some of the nerve fibers might originate from neurons in the brain and/or from a peripheral ganglion.

The expression of PPTA and c-fos mRNA in dog caudal spinal trigeminal nucleus induced by traumatic occlusion / 中华口腔医学杂志

<p><b>OBJECTIVE</b>PPTA and c-fos mRNA expression were detected in dog caudalis subnucleus of trigeminal spinal tract nucleus (VC) induced by trauma occlusion in order to investigate orofacial pain mechanism.</p><p><b>METHODS</b>The occlusal surface of the first and second maxillary right molars in 15 dogs were unilaterally raised 1.5 mm with casting Ni-Cr inlay which were fixed in Class I hole. On days 3, 7, 14, 30 and 60 after teeth operation, the VC of right and left sides were removed. PPTA and c-fos mRNAs were detected in experimental and control groups with reverse transcription-polymerase chain reaction (RT-PCR).</p><p><b>RESULTS</b>(1) The basal levels of PPTA and c-fos mRNAs were extremely low and poorly detectable in VC in control animals. (2) The expression of PPTA mRNA in VC of traumatic side was up regulated from 3 days after inlay was fixed in molar and reached peak level during 14 to 30 days and then down-regulated gradually and no significant difference was noted between 60 days group and control group. (3) c-fos mRNA expression was more intense during 3 to 7 days compared with the control group but undetectable in the other experimental period. (4) Both PPTA and c-fos mRNAs expression in VC of trauma occlusal side were more intense than that in the contralateral side.</p><p><b>CONCLUSIONS</b>The present results show that both PPTA and c-fos mRNA expression are elevated in dog's VC induced by traumatic occlusion. The primary afferent terminal of orofacial area is sensitized, which suggest one kind of mechanism of orofacial pain in the condition of traumatic occlusion.</p>

Tachykinins and airway inflammation

Já está bem estabelecido que a asma é uma doença inflamatória das vias aéreas, com o envolvimento de múltiplos mediadores e células inflamatórias. Um grupo de mediadores que pode estar envolvido na fisiopatologia da asma é um grupo de peptídios denominado neurosininas(ou tauqicininas). As taquicinas, em especial a substância P (SP) e a neurocinina A (NKA), estão presentes nos pulmões de várias espécies de mamíferos, incluindo os seres humanos. Estes peptídios são armazenados em terminações periféricas de nervos sensitivos que são sensíveis à ação da capsaicina. A ativação destas terminações nervosas por uma grande variedade de estímulos físicos ou químicos resulta em liberação de SP e NKA nas vias aéreas. Estes peptídios, ao serem liberados, produzem no sistema respiratório vários efeitos, como contração do músculo liso das vias aéreas, vasodilatação, extravasamento de proteínas plasmáticas, secreção de muco e acúmulo de células inflamatórias. Os efeitos biológicos da SP e da NKA são provavelmente limitados pela degradação enzimática. O papel das taquicininas em modelos experimentais de asma tem sido estudado na última década. Em modelos experimentais, tanto de resposta aguda a desafio antígênico em cobaias sensibilizadas como de inflamação crônica de vias aéreas induzidas por exposições repetidas a um alérgeno. a depleção de taquicininas induzida por tratamento prévio com capsaicina resulta em uma diminuição da resposta mecênica e inflamatória a um desafio com alérgeno. Uma vez que as taquicininas produzem em roedores muitas das alterações observadas na asma, é possível que as taquicininas estejam envolvidas na asma humana. Embora alguns estudos tenham sido feitos em seres humanos, ainda não há evidências conclusivas sobrea a importância das taquicininas na asma humana

Effects of Sensory Denervation by Neonatal Capsaicin Treatment on Cytokine Production and Various Immune Responses / 대한면역학회지

Capsaicin, the pungent principle of hot peppers, is a neurotoxin that depletes unmyelinated primary sensory neurons (polymodal nociceptors) of neuropeptides like tachykinins. However, the role of capsaicin-sensitive sensory nerve in the production of cytokines, penicillin V (PEV)-induced active fatal anaphylaxis and other immune responses is not yet fully established. Neonatal mice were pretreated s.c. with a single injection of 10 ug of capsaicin per mouse in volume of 20 ul within 5 days of age. Using 5-8 week old mice pretreated as neonates with capsaicin, the capsaicin- pretreated and vehicle-treated control mice were examined for various parameters of immune responses described above. For the induction of active fatal anaphylaxis with PEV, 8 week old mice pretreated as neonates and age-matched capsaicin- untreated control mice were sensitized i.p. with 500 ug of PEV-ovalbumin conjugate plus 2*10(9) B. pertussis and 1.0 mg alum and challenged i.v. with PEV-bovine serum albumin conjugate 14 days later. It was found that neonatal capsaicin-pretreatment significantly enhanced contact hypersensitivity to TNCB and hemagglutination response to SRBC, but significantly inhibited the proliferation response of rnurine splenocyte to Con A and LPS. Interestingly, neonatal capsaicin pretreatment significantly inhibited the intensity of PEV-induced active fatal anaphylaxis and decreased the mortality due to anaphylactic shock. It also significantly inhibited LPS- induced production of cytokines such as TNF-a, IL-1B, IL-6, IL-10, and IL-12. The capsaicin-pretreatment also resulted in an inhibition of the activation of NF-kB. Taken together, these data showed for the first time that neonatal capsaicin-pretreatment significantly inhibited an antibiotic (PEV)-induced anaphylaxis and production of various cytokines, and suggest that capsaicin-sensitive primary sensory nerve may play an important regulatory role in active fatal anaphylaxis and cytokine production, thus potentially presenting tools for immune intervention. In particular, the data presented also indicated the possibility to selectively down-modulate cytokine production and NF-kB activation may offer a broad application for therapeutic intervention in neuroimmunological diseases and other pathological situations.

Effects of Capsaicin on Production of Cytokines and Nitric Oxide, Salmonella Infection and NF-kappa B Activation / 대한면역학회지

"Capsaicin, the pungent principle of hot peppers, is a neurotoxin that depletes primary sensory neurons of neuropeptides like tachykinin. The objectives of these experiment was to examine the effects of capsaicin on Salmonel/a typhimurium-induced production of cytokines such as TNF-a, IL-1B, IL-6, IL-10 and IL-12 and on production of nitric oxide in peritoneal macrophages. In addition, the effects of capsaicin on survival rates of S. typhimurium-infected mice and on nuclear transcription factor (NF-kB) activation were also investigated. Mice were pretreated with a single s.c. injection of 100 ug of capsaicin and were infected i.v. with S. typhimurium (5xO5/mouse) in 0.2 ml volume after capsaicin pretreatment. The serum cytokine levels were measured 30, 60, 120, 180 and 240 min after Salmonella infection, using ELISA kits. The activation of NF-B was also examined by gel shift assay in spleens, thymuses and brains of mice that had been pretreated with a single s.c. injection of 100 ug of capsaicin. It was found that Sa/mone/la infection induced the production of TNF-a, IL-1B, IL-6, IL-10 and IL-12, but capsaicin pretreatment inhibited the production of TNF-a, IL-1B, IL-10 and IL-12, but enhanced IL-6 production 120 min after Salmonella infection. Interestingly, the capsaicin pretreatment inhibited the activation of NF-kB in spleens and thymuses. There were no differences in the numbers of bacteria in livers, brains, spleens, kidneys and lungs between capsaicin- pretreated mice and the control animals in applied experimental conditions. Suprisingly, however, capsaicin pretreatment increased both the survival rates of Sa/mone//a-infected mice and production of nitric oxide by peritoneal macrophages compared with capsaicin-untreated control mice. Taken together, these results indicate that the capsaicin-sensitive primary sensory neurons may play an important modulatory role in the production of cytokine, nitric oxide and NF-B activation and the pathogenesis of salmonellosis."

A polymerphism of the angiorensin-converting enzyme gene according to the asthma severity / 천식및알레르기

BACKGROUND: The angiotensin-converting enzyme (ACE) has a major role in the degradation of bradykinin, tachykinin, substance P which are associated with bronchial hyperresponsiveness and inflammation. The other role of ACE is the genesis of angiotensin II which causes bronchial smooth muscle contraction. The deletion polymorphism of ACE gene(DDtype) may be related to the high serum level of ACE. OBJECTIVE: We studied to evaluate an association between the insertion /deletion polymorphism of the ACE gene and asthma, and its severity. Materials and methods: Sixty asthmatic patients and 44 healthy controls were enrolled. Severity of asthma was classified by the guideline of NHLBI/WHO workshop. The ACE genotypes of all the subjects were determined by polymerase chain reaction. RESULTS: The distribution of ACE genotypes were not significantly different between healthy controls and asthma group (p)0.05). In asthmatic patients, the genetic polymorphism was similar between different severity groups (p) 0.05). Conchcsion: It is suggested that I/D polymorphism of the ACE gene may not be associated with development of asthma. The severity of asthma may not be influenced by I/D polymorphism of the ACE gene.

NMR and molecular dynamics studies of tachykinins: conformation of the C-terminal pentapeptide of substance P(SP7-11).

Substance P belongs to the tachykinin family of neuropeptides which exhibit diverse pharmacological activity. The conformation of Phe1-Phe2-Gly3-Leu4-Met5-NH2 the C-terminal pentapeptide of substance P (SP7-11) has been studied by NMR and molecular dynamics (MD) methods. NMR studies were carried out both in DMSO-d6 and 95% H2O. Based on the observed chemical shifts, 3JNH alpha coupling constants, temperature coefficients of chemical shifts of NH resonances and the pattern of inter- and intraresidue NOE's, a predominantly extended backbone conformation has been deduced for the peptide in both DMSO and H2O. MD calculations carried out in vacuo indicate that the global minimum energy conformation of the molecule is folded with an intramolecular hydrogen bond between the protonated N-terminal and the C-terminal CONH2 group. The simulation shows that beta-turns are energetically unfavourable, while alpha-helices are seen to be unstable for the peptide. gamma-Bends at either Gly3 or Leu4 are the most preferred ones. Simulations carried out in DMSO as well as in water show a preference for a nearly extended conformation.

Effects of Substance P on the Cell Proliferation and IL-2 Production of T Lymphocyte / 대한치주과학회지

Immune responses of periodontal tissue may be regulated by products of sensory afferent nerve endings such as neuropeptides. Substance P(SP), a tachykinin neuropeptide, has been previously reported to stimulate the activities of T lymphocyte. Therefore, I examined the role of SP in IL-2 production and cell proliferation by using a homogeneous line of T lymphocytes(Jurkat and HuT78). Cell proliferation rate was determined by [3H]-thymidine incorporation test, and IL-2 was quantitated by the growth rate of CD4+ IL-2-dependent T lymphocyte line CTLL-2. SP stimulated cell proliferation of T lymphocytes at the concentration of 10(-12) and 10(-8)M in a biphasic bell-shape dose-dependent manner. However, SP alone did not induce IL-2 release at the concentration range of 10(-6) to 10(-14)M. The upregulation of IL-2 release was observed when 10(-12)M SP was applied together with mitogens such as Con A or PHA+PMA on T cell lines, especially on Jurkat. Con A or PHA+PMA demonstrated to increase the rate of cell proliferation of Jurkat, which had shown to produce much amount of IL-2 indicating that mitogen-induced cell proliferation might be partially influenced by released IL-2. It was concluded that regulatory effects of SP on the immune/inflammatory response could be mediated through the costimulatory upregulation of IL-2 production and increase of cell proliferation of T lymphocyte.

Effect of Capsaicin on Immune Responses, Anaphylaxis and Tumorigenesis in Mice / 대한면역학회지

It has been known that the interconnection between the gervous, endocrine and immune system are largely mediated through regulatory soluble factors such as neruopeptides, cytokines and hormones. Capsaicin, the pungent principle of hot peppers, is a neurotoxin that affects primary sensory neurons of the C and A-b type and depletes primary sensory neurons (polymodal nociceptors) of neuropeptides like tachykinin. In this study capsaicin was used to explore the possible role of the neruons on the expression of cellular and humoral immune responses and TNF-a prodcution. Mice were pretreated with s.c. injections in the neck region with a single dose of 100 u,g of capsaicin per mouse before immunization. ...continue...

Neuropeptide control of the cardiovascular system in fish and reptiles

Accumulating evidence shows the involvement of neuropeptides in cardiovascular control in mammals as well as non-mammalian species. Our own immunohistochemical studies indicate a sparse innervation only in cyclostomes, holostean fish and lungfish, a more extensive variation and distribution in elasmobranchs and teleosts, and a rich and varied innervation of the cardiovascular system in crocodiles and lizards. Vasoactive intestinal polypeptide (VIP), neuropeptide Y (NPY), gastrin releasing peptide (GRP) and tachykinins are present in most vertebrate groups. VIP is vasodilatory in the Atlantic cod (Gadus morhua) as in most mammalian species, but increases gut vascular resistance in the spiny dogfish (Squalus acanthias). NPY potentiates the effect of noradrenaline on skate (Raja rhina) coronary vessels, suggesting an interaction between adrenergic mechanisms and NPY early in evolution, but studies in the spiny dogfish and the crocodile also demonstrate different mechanisms for the action of NPY and adrenaline in some species. Bombesin/GRP increases flow to the gut in the spiny dogfish by an increase in somatic vascular resistance, while visceral resistance remains unchanged. In the caiman (Caiman crocodylus crocodylus) bombesin causes a shunting of blood from the lung to the gut. Substance P and other tachykinins in general increase flow to the gut, and on some occasions also increase somatic blood flow. Flow in the anastomosis of the crocodile (Crocodylus porosus) gut is increased by substance P. The results presented here are a review of several published and unpublished studies.

Effects of FK224, a NK1 and NK2 Receptor Antagonist, on Plasma Extravasation of Neurogenic Inflammation in Rat Airways / 결핵

BACKGROUND: Asthma is an inflammatory disease because there are many inflammatory changes in the asthmatic airways. Axon reflex mechanisms may be involved in the pathogenesis of asthma. Sensory neuropeptides are involved in this inflammation, which is defined as neurogenic inflammation. Substance p, neurokinin A, and neurokinin B may be main neuropeptides of neurogenic inflammation in airways. These tachykinins act on neurokinin recptors. Three types of neurokinin receptors, such as NK1, NK2, and NK3, are currently recognized, at which substance p,neurokinin A, and neurokinin B may be the most relvant natural agonist of neurogenic inflammation in airways. The receptor subtypes present in several tissues have been characterized on the basis of differential sensitivity to substance p, neurokinin A, and neurokinin B. Plasma extravasation and vasodilation are induced by substance p more potently than by neurokinin A, indicating NK1 receptors on endothelial cells mediate the response. But airway contraction is induced by neurokinin A more potently than by substance P, indicating the NK2 receptors in airway smooth muscles. These receptors are used to evaulate the pathogenesis of brochial asthma. FK224 was identified from the fermentation products of Streptomyces violaceoniger. FK224 is a dual antagonist of both NK1 and NK2 recptors. PURPOSE: For a study of pathogenesis of bronchial asthma, the effect of FK224 on plasma extravasation induced by vagal NANC electrical stimulation was evaluated in rat airway. METHOD: Male Sprague-Dawley rats weighing 180~450gm were anesthetized by i.p. injection of urethane. Plasma extravasation was induced by electrical stimulation of cervical vagus NANC nerves with 5Hz, 1mA, and 5V for 2 minutes(NANC2 group) and for sham operation without nerve stimulation(control group). To evaluate the effect of FK224 on plasma extravasation in neurogenic inflammation, FK224(lmg/kg, Fujisawa Pharmaceutical Co., dissolved in dimethylsul- phoxide; DMSO, Sigma Co.) was injected 1 min before nerve stimulation(FK224 group). To assess plasma exudation, Evans blue dye(20mg/kg,dissolved in saline) was used as a plasma marker and was injected before nerve stimulation. After removal of intravascular dye, the evans blue dye in the tissue was extracted in formamide(37degreesC, 24h) and quantified spectrophotometrically by measuring dye absorbance at 629nm wavelength. Tissue dye content was expressed as ng of dye per mg of wet weight tissue. The amount of plasma extravasation was measured on the part of airways in each groups. RESULTS: 1) Vagus nerve(NANC) stimulation significantly increased plasma leakage in trachea, main bronchus, and peripheral bronchus compared with control group, 14.1 +/-1.6 to 49.7+/-2.5, 17.5 +2.0 to 38.7 +/-2.8, and 12.7+/-2.2 to 19.1 +/-1.6ng of dye per mg of tissue(mean +/- SE), respectively(p0.05) 2) FK224 had significant inhibitory effect upon vagal nerve stimulation-induced airway plasma leakage in any airway tissues of rat,such as trachea, main bronchus, and peripheral bronchus compared with vagus nerve stimulation group, 49%, 58%, and 70%, respectively(p<0.05). Inhibitory effect of FK224 on airway plasma leakage in neurogenic inflammation was revealed the more significant in peripheral bronchus, but no significant in lung parenchyma. CONCLUSION: These results suggest that FK224 is a selective NK receptor antagonist which effectively inhibits airway plasma leakage induced by the endogenous neurotransmitters relased by neurogenic inflammation in rat airway. Tachykinin receptor antagonists may be useful in the treatment of brochial asthma.