Abstract
Intestinal functions are under the control of extrinsic afferent neurons, extrinsic efferent neurons of the sympathetic and parasympathetic autonomic nervous system and the intrinsic neurons of the enteric nervous system. Apart from the classical transmitters acetylcholine and noradrenaline, these neurons express a variety of neuropeptides including the tachykinins substance P (SP) and neurokinin A (NKA), calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP) and neuropeptide Y [1]. Nerve activity leads to exocytotic release of the peptides which, by interacting with specific receptors on postjunctional neurons or effector cells, participate in the regulation of gastrointestinal motility, secretion, circulation and tissue homeostasis. After recognition of the physiological roles of peptidergic neurons and neuropeptides in the gut it is becoming increasingly evident that gastrointestinal inflammation and other disorders may be related to imbalanced function of certain neuropeptide systems. The conjecture that neuropeptides have a bearing on gastrointestinal disease has been most advanced for SP, NKA and CGRP, and it is with these peptides that the present article is concerned.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Costa M, Furness JB, Gibbins IL (1986) Chemical coding of enteric neurons. Prog Brain Res 68: 217–239
Nakanishi S (1987) Substance P precursor and kininogen: their structures, gene organi-zations, and regulation. Physiol Rev 67: 1117–1142
Holzer P, Holzer-Petsche U (1997) Tachykinins in the gut. Part I. Expression, release and motor function. Pharmacol Ther 73: 173–217
Holzer P (1994) Calcitonin gene-related peptide. In: JH Walsh, GJ Dockray (eds): Gut peptides: Biochemistry and physiology. Raven Press, New York, 493–523
Wimalawansa SJ (1996) Calcitonin gene-related peptide and its receptors: molecular genetics, physiology, pathophysiology, and therapeutic potentials. Endocrine Rev 17: 533–585
Furness JB, Bornstein JC, Murphy R, Pompolo S (1992). Roles of peptides in transmis-sion in the enteric nervous system. Trends Neurosci 15: 66–71
Costa M, Brookes SJH, Steele PA, Gibbins I, Burcher E, Kandiak CJ (1996) Neuro-chemical classification of myenteric neurons in the guinea-pig ileum. Neuroscience 75: 949–967
Ekblad E, Winther C, Ekman R, Håkanson R, Sundler F (1987) Projections of pep-tide-containing neurons in rat small intestine. Neuroscience 20: 169–188
Holzer P (1992) Peptidergic sensory neurons in the control of vascular functions: mechanisms and significance in the cutaneous and splanchnic vascular beds. Rev Physiol Biochem Pharmacol 121: 49–146
Green T, Dockray GJ (1988) Characterization of the peptidergic afferent innervation of the stomach in the rat, mouse and guinea-pig. Neuroscience 25: 181–193
Bäck N, Ahonen M, Häppölä O, Kivilaakso E, Kiviluoto T (1994) Effect of vagotomy on expression of neuropeptides and histamine in rat oxyntic mucosa. Digest Dis Sci 39: 353–361
Suzuki T, Kagoshima M, Shibata M, Inaba N, Onodera S, Yamaura T, Shimada H (1997) Effects of several denervation procedures on distribution of calcitonin gene-related peptide and substance P immunoreactive fibers in rat stomach. Digest Dis Sci 42: 1242–1254
Sternini C (1992) Enteric and visceral afferent CGRP neurons. Targets of innervation and differential expression patterns. Ann New York Acad Sci 657: 170–186
Mulderry PK, Ghatei MA, Spokes RA, Jones PM, Pierson AM, Hamid QA, Kanse S, Amara SG, Burrin JM, Legon S, Polak JM, Bloom SR (1988) Differential expression of α-CGRP and β-CGRP by primary sensory neurons and enteric autonomic neurons of the rat. Neuroscience 25: 195–205
Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389: 816–824
Geppetti P, Tramontana M, Evangelista S, Renzi D, Maggi CA, Fusco BM, Del Bianco E (1991) Differential effect on neuropeptide release of different concentrations of hydrogen ions on afferent and intrinsic neurons of the rat stomach. Gastroenterology 101: 1505–1511
Manela FD, Ren J, Gao J, McGuigan JE, Harty RF (1995) Calcitonin gene-related peptide modulates acid-mediated regulation of somatostatin and gastrin release from rat antrum. Gastroenterology 109: 701–706
Nakanishi S (1991) Mammalian tachykinin receptors. Annu Rev Neurosci 14: 123–136
Maggi CA (1995) The mammalian tachykinin receptors. Gen Pharmacol 26: 911–944
Regoli D, Boudon A, Fauchère JL (1994) Receptors and antagonists for substance P and related peptides. Pharmacol Rev 46: 551–599
Aiyar N, Rand K, Elshourbagy NA, Zeng ZZ, Adamou JE, Bergsma DJ, Li YA (1996) A cDNA encoding the calcitonin gene-related peptide type 1 receptor. J Biol Chem 271: 11325–11329
Sternini C, Su D, Gamp PD, Bunnett NW (1995) Cellular sites of expression of the neurokinin-1 receptor in the rat gastrointestinal tract. J Comp Neurol 358: 531–540
Portbury AL, Furness JB, Young HM, Southwell BR, Vigna SR (1996) Localisation of NK1 receptor immunoreactivity to neurons and interstitial cells of the guinea-pig gastrointestinal tract. J Comp Neurol 367: 342–351
Grady EE Baluk P, Böhm S, Gamp PD, Wong H, Payan DG, Ansel J, Portbury AL, Furness JB, McDonald DM, Bunnett NW (1996) Characterization of antisera specific to NK1, NK2 and NK3 neurokinin receptors and their utilization to localize receptors in the rat gastrointestinal tract. J Neurosci 16: 6975–6986
Portbury AL, Furness JB, Southwell BR, Wong H, Walsh JH, Bunnett NW (1996) Distribution of neurokinin-2 receptors in the guinea-pig gastrointestinal tract. Cell Tissue Res 286: 281–292
Mann PT, Southwell BR, Ding Y-Q, Shigemoto R, Mizuno N, Furness JB (1997) Localisation of neurokinin 3 (NK3) receptor immunoreactivity in the rat gastrointestinal tract. Cell Tissue Res 289: 1–9
Holzer P (1997) Involvement of nitric oxide in the substance P-induced inhibition of intestinal peristalsis. NeuroReport 8: 2857–2860
Holzer P, Lippe IT, Heinemann A, Barthó L (1998) Tachykinin NK1 and NK2 receptor-mediated control of peristaltic propulsion in the guinea-pig small intestine in vitro. Neuropharmacology 37: 131–138
Holzer P, Holzer-Petsche U (1997) Tachykinins in the gut. Part II. Roles in neural excitation, secretion and inflammation. Pharmacol Ther 73: 219–263
Holzer P (1998) Neural emergency system in the stomach. Gastroenterology 114: 823–839
Moore BA, Vanner S, Bunnett NW, Sharkey KA (1997) Characterization of neurokinin1 receptors in the submucosal plexus of guinea pig ileum. Am J Physiol 273: G670–G678
Figini M, Emanueli C, Grady EF, Kirkwood K, Payan DG, Ansel J, Gerard C, Geppetti P, Bunnett NW (1997) Substance P and bradykinin stimulate plasma extravasation in the mouse gastrointestinal tract and pancreas. Am J Physiol 272: G785–G793
Prystowsky JB, Rege RV (1997) Neurogenic inflammation in cholecystitis. Digest Dis Sci 42: 1489–1494
Renzi D, CalabrĂł A, Panerai C, Tramontana M, Evangelista S, Milani S, Surrenti C (1994) Preprotachykinin mRNA expression in the colonic tissue during experimental colitis in rats. Digestion 55 (Suppl 2): 36
Renzi D, Tramontana M, Panerai C, Surrenti C, Evangelista S (1992) Decrease of calcitonin gene-related peptide, but not vasoactive intestinal polypeptide and substance P, in the TNB-induced experimental colitis in rats. Neuropeptides 22: 56–57
Reinshagen M, Patel A, Sottili M, French S, Sternini C, Eysselein VE (1996) Action of sensory neurons in an experimental rat colitis model of injury and repair. Am J Physiol 270: G79–G86
Eysselein VE, Reinshagen M, Cominelli F, Sternini C, Davis W, Patel A, Nast CC, Bernstein D, Anderson K, Khan H, Snape WJ (1991) Calcitonin gene-related peptide and substance P decrease in the rabbit colon during colitis. A time study. Gastroenterology 101: 1211–1219
Reinshagen M, Adler G, Eysselein VE (1995) Substance P gene expression in acute experimental colitis. Regul Pept 59: 53–58
Kishimoto S, Kobayashi H, Machino H, Tari A, Kajiyama G, Miyoshi A (1994) High concentrations of substance P as a possible transmission of abdominal pain in rats with chemical induced ulcerative colitis. Biomed Res 15 (Suppl 2): 133–140
Esposito V, Linard C, Maubert C, Aigueperse J, Gourmelon P (1996) Modulation of gut substance P after whole-body irradiation: a new pathological feature. Digest Dis Sci 41: 2070–2077
Bost KL, Breeding SA, Pascual DW (1992) Modulation of the mRNAs encoding substance P and its receptor in rat macrophages by LPS. Reg Immunol 4: 105–112
Bost KL (1995) Inducible preprotachykinin mRNA expression in mucosal lymphoid organs following oral immunization with Salmonella. J Neuroimmunol 62: 59–67
Castagliuolo I, Keates AC, Qiu BS, Kelly CP, Nikulasson S, Leeman SE, Pothoulakis C (1997) Increased substance P responses in dorsal root ganglia and intestinal macrophages during Clostridium difficile toxin A enteritis in rats. Proc Natl Acad Sci USA 94: 4788–4793
Mantyh CR, Vigna SR, Maggio JE, Mantyh PW, Bollinger RR, Pappas TN (1994) Substance P binding sites on intestinal lymphoid aggregates and blood vessels in inflammatory bowel disease correspond to authentic NK-1 receptors. Neurosci Lett 178: 255–259
Mantyh CR, Vigna SR, Bollinger RR, Mantyh PW, Maggio JE, Pappas TN (1995) Differential expression of substance P receptors in patients with Crohn’s disease and ulcerative colitis. Gastroenterology 109: 850–860
Mantyh CR, Maggio JE, Mantyh PW, Vigna SR, Pappas TN (1996) Increased substance P receptor expression by blood vessels and lymphoid aggregates in Clostridium difficile-induced pseudomembranous colitis. Digest Dis Sci 41: 614–620
Barthó L, Holzer P (1995) The inhibitory modulation of guinea-pig intestinal peristalsis caused by capsaicin involves calcitonin gene-related peptide and nitric oxide. NaunynSchmiedeberg’s Arch Pharmacol 353: 102–109
Blackshaw LA, Dent J (1997) Lower oesophageal sphincter responses to noxious oesophageal chemical stimuli in the ferret: involvement of tachykinin receptors. J Auton Nery Syst 66: 189–200
Fargeas MJ, Fioramonti J, Buùno L (1993) Involvement of capsaicin-sensitive afferent nerves in the intestinal motor alterations induced by intestinal anaphylaxis in rats. Int Arch Allergy Immunol 101: 190–195
Croci T, Landi M, Emonds-Alt X, Le Fur G, Maffrand J-P, Manara L (1997) Role of tachykinins in castor oil diarrhoea in rats. Br J Pharmacol 121: 375–380
Shea-Donohue T, Goldhill JM, Montcalm-Mazzilli E, Colleton C, Pineiro-Carrero VM, Sjogren RW (1997) Role of sensory afferents in the myoelectric response to acute enteric inflammation in the rabbit. Am J Physiol 273: G447–G455
Otsuka M, Yoshioka K (1993) Neurotransmitter functions of mammalian tachykinins. Physiol Rev 73: 229–308
Friese N, Diop L, Chevalier E, Angel F, Rivière PJM, Dahl SG (1997) Involvement of prostaglandins and CGRP-dependent sensory afferents in peritoneal irritation-induced visceral pain. Regul Pept 70: 1–7
Goldhill JM, Shea-Donohue T, Ali N, Pineiro-Carrero VM (1997) Tachykininergic neurotransmission is enhanced in small intestinal circular muscle in a rabbit model of inflammation. J Pharmacol Exp Ther 282: 1373–1378
Pothoulakis C, Castagliuolo I, LaMont JT, Jaffer A, O’Keane JC, Snider RM, Leeman SE (1994) CP-96,345, a substance P antagonist, inhibits rat intestinal responses to Clostridium difficile toxin A but not cholera toxin. Proc Natl Acad Sci USA 91: 947–951
Castagliuolo I, LaMont JT, Letourneau R, Kelly C, O’Keane JC, Jaffer A, Theoharides TC, Pothoulakis C (1994) Neuronal involvement in the intestinal effects of Clostridium difficile toxin A and Vibrio cholerae enterotoxin in rat ileum. Gastroenterology 107: 657–665
Eutamene H, Theodorou V, Fioramonti J, Buùno L (1995) Implication of NK1 and NK2 receptors in rat colonic hypersecretion induced by interleukin1: role of nitric oxide. Gastroenterology 109: 483–489
Maggi CA (1997) The effects of tachykinins on inflammatory and immune cells. Regul Pept 70: 75–90
Kraneveld AD, Buckley TL, van Heuven-Nolsen D, van Schaik Y, Koster AS, Nijkamp FP (1995) Delayed-type hypersensitivity-induced increase in vascular permeability in the mouse small intestine: inhibition by depletion of sensory neuropeptides and NK1 receptor blockade. Br J Pharmacol 114: 1483–1489
Kataeva G, Agro A, Stanisz AM (1994) Substance P-mediated intestinal inflammation: inhibitory effects of CP 96,345 and SMS 201–995. Neuroimmunomodulation 1: 350–356
McCafferty D-M, Sharkey KA, Wallace JL (1994) Beneficial effects of local or systemic lidocaine in experimental colitis. Am J Physiol 266: G560–G567
Weinstock JV, Blum AM (1990) Release of substance P by granuloma eosinophils in response to secretagogues in murine schistosomiasis Mansoni. Cell Immunol 125: 380–385
Metwali A, Blum AM, Ferraris L, Klein JS, Fiocchi C, Weinstock JV (1994) Eosinophils within the healthy or inflamed human intestine produce substance P and vasoactive intestinal peptide. J Neuroimmunol 52: 69–78
Lambrecht N, Burchert M, Respondek M, Müller KM, Peskar BM (1993) Role of calcitonin gene-related peptide and nitric oxide in the gastroprotective effect of capsaicin in the rat. Gastroenterology 104: 1371–1380
Stroff T, Plate S, Seyed Ebrahim J, Ehrlich K-H, Respondek M, Peskar BM (1996) Tachykinin-induced increase in gastric mucosal resistance: role of primary afferent neurons, CGRP, and NO. Am J Physiol 271: G1017–G1027
Goso C, Evangelista S, Tramontana M, Manzini S, Blumberg PM, Szallasi A (1993) Topical capsaicin administration protects against trinitrobenzene sulfonic acid-induced colitis in the rat. Eur J Pharmacol 249: 185–190
Evangelista S, Maggi CA, Rovero P, Patacchini R, Giuliani S, Giachetti A (1990) Analogs of neurokinin A(4–10) afford protection against gastroduodenal ulcers in rats. Peptides 11: 293–297
Holzer P, Livingston EH, Guth PH (1991) Sensory neurons signal for an increase in rat gastric mucosal blood flow in the face of pending acid injury. Gastroenterology 101: 416–423
Takeuchi K, Matsumoto J, Ueshima K, Okabe S (1991) Role of capsaicin-sensitive afferent neurons in alkaline secretory response to luminal acid in the rat duodenum. Gastroenterology 101: 954–961
Karmeli F, Eliakim R, Okon E, Rachmilewitz D (1991) Gastric mucosal damage by ethanol is mediated by substance P and prevented by ketotifen, a mast cell stabilizer. Gastroenterology 100: 1206–1216
Buùno L, Fioramonti J, Delvaux M, Frexinos J (1997) Mediators and pharmacology of visceral sensitivity: from basic to clinical investigations. Gastroenterology 112: 1714–1743
Maggi CA (1997) Tachykinins as peripheral modulators of primary afferent nerves and visceral sensitivity. Pharmacol Res 36: 153–169
Holzer-Petsche U, Rordorf-Nikolić T (1995) Central versus peripheral site of action of the tachykinin NKl-antagonist RP 67580 in inhibiting chemonociception. Br J Pharmacol 115: 486–490
Julia V, Buùno L (1997) Tachykininergic mediation of viscerosensitive responses to acute inflammation in rats: role of CGRP. Am J Physiol 272: G141–G146
Plourde V, St.-Pierre S, Quirion R (1997) Calcitonin gene-related peptide in viscerosensitive response to colorectal distension in rats. Am J Physiol 273: G191–G196
Lew WY, Longhurst JC (1986) Substance P, 5-hydroxytryptamine, and bradykinin stimulate abdominal visceral afferents. Am J Physiol 250: R465–R473
Barber WD, Burks TF (1987) Brain-gut interactions: brain stem neuronal response to local gastric effects of substance P. Am J Physiol 253: G369–G377
Julia V, Morteau O, Buéno L (1994) Involvement of neurokinin 1 and 2 receptors in viscerosensitive response to rectal distension in rats. Gastroenterology 107: 94–102
Urban L, Thompson SWN, Dray A (1994) Modulation of spinal excitability: co-opera-tion between neurokinin and excitatory amino acid neurotransmitters. Trends Neurosci 17: 432–438
Kaneko H, Mitsuma T, Uchida K, Furusawa A, Morise K (1993) Immunoreactivesomatostatin, substance P, and calcitonin gene-related peptide concentrations of the human gastric mucosa in patients with nonulcer dyspepsia and peptic ulcer disease. Am J Gastroenterol 88: 898–904
McLean PG, Picard C, Garcia-Villar R, Moré J, Fioramonti J, Buéno L (1997) Effects of nematode infection on sensitivity to intestinal distension: role of tachykinin NK2 receptors. Eur J Pharmacol 337: 279–282
Evangelista S, Renzi D, Tramontana M, Surrenti C, Theodorsson E, Maggi CA (1992) Cysteamine induced-duodenal ulcers are associated with a selective depletion in gastric and duodenal calcitonin gene-related peptide-like immunoreactivity in rats. Regul Pept 39: 19–28
Evangelista S, Renzi D, Mantellini P, Surrenti C, Meli A (1990) Duodenal SP-like immunoreactivity is decreased in experimentally-induced duodenal ulcers. Neurosci Lett 112: 352–355
Swain MG, Agro A, Blennerhassett P, Stanisz A, Collins SM (1992) Increased levels of substance P in the myenteric plexus of Trichinella-infected rats. Gastroenterology 102: 1913–1919
Hellström PM, Al Saffar A, Ljung T, Theodorsson E (1997) Endotoxin actions on myoelectric activity, transit, and neuropeptides in the gut: role of nitric oxide. Digest Dis Sci 42: 1640–1651
Masson SD, McKay DM, Stead RH, Agro A, Stanisz A, Perdue MH (1996) Nippostrongylus brasiliensis infection evokes neuronal abnormalities and alterations in neurally regulated electrolyte transport in rat jejunum. Parasitology 113: 173–182
Kimura M, Masuda T, Hiwatashi N, Toyota T, Nagura H (1994) Changes in neuropeptide-containing nerves in human colonic mucosa with inflammatory bowel disease. Pathol Int 44: 624–634
Belai A, Boulos PB, Robson T, Burnstock G (1997) Neurochemical coding in the small intestine of patients with Crohn’s disease. Gut 40: 767–774
Koch TR, Carney JA, Go VL (1987) Distribution and quantitation of gut neuropeptides in normal intestine and inflammatory bowel diseases. Digest Dis Sci 32: 369–376
Bernstein CN, Robert ME, Eysselein VE (1993) Rectal substance P concentrations are increased in ulcerative colitis but not in Crohn’s disease. Am J Gastroenterol 88: 908–913
Keranen U, Kiviluoto T, Järvinen H, Bäck N, Kivilaakso E, Soinila S (1995) Changes in substance P-immunoreactive innervation of human colon associated with ulcerative colitis. Digest Dis Sci 40: 2250–2258
Plourde V, Wong HC, Walsh JH, Raybould HE, Taché Y (1993) CGRP antagonists and capsaicin on celiac ganglia partly prevent postoperative gastric ileus. Peptides 14: 1225–1229
Espat NJ, Cheng G, Kelley MC, Vogel SB, Sninsky CA, Hocking MP (1995) Vasoactive Peter Holzer intestinal peptide and substance P receptor antagonists improve postoperative ileus. J Surg Res 58: 719–723
Ikeda K, Miyata K, Orita A, Kubota H, Yamada T, Tomioka K (1995) RP67580, a neurokininl receptor antagonist, decreased restraint stress-induced defecation in rat. Neurosci Lett 198: 103–106
Castagliuolo I, LaMont JT, Qiu BS, Fleming SM, Bhaskar KR, Nikulasson ST, Komet-sky C, Pothoulakis C (1996) Acute stress causes mucin release from rat colon: role of corticotropin releasing factor and mast cells. Am J Physiol 271: G884–G892
Eutamene H, Theodorou V, Fioramonti J, Buéno L (1997) Rectal distention-induced colonic net water secretion in rats involves tachykinins, capsaicin sensory, and vagus nerves. Gastroenterology 112: 1595–1602
Bass BL, Trad KS, Harmon JW, Hakki FZ (1991) Capsaicin-sensitive nerves mediate esophageal mucosal protection. Surgery 110: 419–426
Leung FW (1993) Primary sensory neurons mediate in part the protective mesenteric hyperemia after intraduodenal acidification in rats. Gastroenterology 105: 1737–1745
Maggi CA, Evangelista S, Abelli L, Somma V, Meli A (1987) Capsaicin-sensitive mechanisms and experimentally induced duodenal ulcers in rats. J Pharm Pharmacol 39: 559–561
Takeuchi K, Matsumoto J, Ueshima K, Ohuchi T, Okabe S (1992) Induction of duodenal ulcers in sensory deafferented rats following histamine infusion. Digestion 51: 203–210
Evangelista S, Maggi CA, Meli A (1987) Involvement of capsaicin-sensitive mechanism(s) in the antiulcer defence of intestinal mucosa in rats. Proc Soc Exp Biol Med 184: 264–266
Evangelista S, Tramontana M (1993) Involvement of calcitonin gene-related peptide in rat experimental colitis. J Physiol (Paris) 87: 277–280
Evangelista S, Meli A (1989) Influence of capsaicin-sensitive fibres on experimentally-induced colitis in rats. J Pharmac Pharmacol 41: 574–575
McCafferty D-M, Wallace JL, Sharkey KA (1997) Effects of chemical sympathectomy and sensory nerve ablation on experimental colitis in the rat. Am J Physiol 272: G272–G280
Leung FW (1992) Role of capsaicin-sensitive afferent nerves in mucosal injury and injury-induced hyperemia in rat colon. Am J Physiol 262: G332–G337
Reinshagen M, Patel A, Sottili M, Nast C, Davis W, Mueller K, Eysselein V (1994) Protective function of extrinsic sensory neurons in acute rabbit experimental colitis. Gastroenterology 106: 1208–1214
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1999 Springer Basel AG
About this chapter
Cite this chapter
Holzer, P. (1999). Neuropeptides and the gut: Tachykinins and calcitonin gene-related peptide in intestinal inflammation and pain. In: Brain, S.D., Moore, P.K. (eds) Pain and Neurogenic Inflammation. Progress in Inflammation Research. Birkhäuser, Basel. https://doi.org/10.1007/978-3-0348-8753-3_12
Download citation
DOI: https://doi.org/10.1007/978-3-0348-8753-3_12
Publisher Name: Birkhäuser, Basel
Print ISBN: 978-3-0348-9758-7
Online ISBN: 978-3-0348-8753-3
eBook Packages: Springer Book Archive