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Tachykinins in the Gut. Part II. Roles in Neural Excitation, Secretion and Inflammation

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Tachykinins in the Gut. Part II. Roles in Neural Excitation, Secretion and Inflammation Pfxnma~ol.Ther. Vol. 73, No. 3, pp. 219-263, 1997 ISSN 0163-7258197$32.00 CopyrIght0 1997 ElsevierScience Inc. PI1 SO163-7258(96)00196-9 ELSEVIER A.wciate Editor: 1. We&r Tachykinins in the Gut. Part II. Roles in Neural Excitation, Secretion and Inflammation Peter Holzer” and Ulrike Holw-er-Pets&e DEPARTMENT0FEXPERIMENTALANDCLINlCALPHARMACOLOGY,UNIVERSlTYOFGRAZ,UNlVERSITiiTSPLATZ4,A-8010GRAZ,AUSTRIA ABSTRACT. The preprotachykinin-A gene-derived peptides substance (substance P; SP) and neurokinin (NK) A are expressed in intrinsic enteric neurons, which supply all layers of the gut, and extrinsic primary afferent nerve fibers, which innervate primarily the arterial vascular system. The actions of tachykinins on the digestive effector systems are mediated by three different types of tachykinin receptor, termed NK,, NKr and NK, receptors. Within the enteric nervous system, SP and NKA are likely to mediate, or comediate, slow synaptic transmission and to modulate neuronal excitability via stimulation of NK, and NK, receptors. In the intestinal mucosa, tachykinins cause net secretion of fluid and electrolytes, and it appears as if SP and NKA play a messenger role in intramural secretory reflex pathways. Secretory processes in the salivary glands and pancreas are likewise influenced by tachykinins. The gastrointestinal arterial system may be dilated or constricted by tachykinins, whereas constriction and an increase in the vascular permeability are the only effects seen in the venous system. Various gastrointestinal disorders are associated with distinct changes in the tachykinin system, and there is increasing evidence that tachykinins participate in the hypersecretory, vascular and immunological disturbances associated with infection and inflammatory bowel disease. In a therapeutic perspective, it would seem conceivable that tachykinin antagonists could be exploited as antidiarrheal, anti- inflammatory and antinociceptive drugs. PHAFMACOL. THER. 73(3): 219-263,1997. 0 1997 Elsevier Science Inc. KEYWORDS. Substance P, neurokinin A, enteric nervous system, primary afferent neurons, intestinal secretion, inflammatory bowel disease. CONTENTS 1. INTRODUCTION. .220 4.4. PHYSIOLOGICALROLES 0~ 2. OCCURRENCE OF TACHYKININS IN THE TACHYRININSINSALIVARY MUCOSAL,GLANDuLARANDVASCULAR SECRETION. ,229 SYSTEMSOFTHEGUT. .221 5. TACHYRININSANDGASTRICSECRETION .230 2.1. OVERVIEW. .221 5.1. OVERVIEW. .230 2.2. TACHYRININS IN THE 5.2. TACHYRININEFFECTSONEXOCRINE GASTROINTESTINALMUCOSA. .221 GASTRIC SECRETION . .230 2.3. TACHYRININSINTHEVASCULAR 5.2.1.FLUIDANDACID SECRETION SYSTEMOFTHEGUT . .222 INTOTHESTOMACH. .230 2.4. TACHYRININSIN THESALIVARY 5.2.2.PEPSINOGEN SECRETION INTO GLANDS . ..223 THESTOMACH. ..231 2.5. TACHYRININSINTHE 5.2.3.Mucus ANDBICARBONATE HEPATOBILIARYSYSTEM . .223 SECRETION INTO 2.6. TACHYRININSINTHEPANCREAS. .224 THESTOMACH. .231 3. EFFECTSOFTACHYRININSONENTERIC 5.3. TACHYRININEFFECTSON NEURONS . .224 ENDOCRINEGASTRICSECRETION. .231 3.1. OVERVIEW. .224 6. TACHYRININSANDINTESTINAL 3.2. MEMBRANEACTIONSOF SECRETION . .231 TACHYKININSONENTERIC 6.1. OVERVIEW. .231 NEURONS . .224 6.2. SECRETORYEFFECTSOF 3.3. TACHYRININ-EVOREDRELEASEOF TACHYRININSINTHE ENTERICNEUROTRANSMITTERS . .225 INTESTINE. .231 3.4. PHYSIOLOGICALIMPLICATIONSOF 6.2.1. RECEPTORS ANDMEDIATOR TACHYKININSASMEDIATORSOFTHE SYSTEMSINVOLVEDINTHEIN SLOWEXCITATORYPOSTSYNAPTIC VIVOSECRETORYEFFECTSOF POTENTIAL . .227 TACHYKININS . .231 4. TACHYRININSANDSALIVARY 6.2.2. RECEPTORSANDMEDIATOR SECRETION . .228 SYSTEMSINVOLVEDINTHEIN 4.1. OVERVIEW. .228 VITROSECRETORYEFFECTSOF 4.2. TACHYRININEFFECTSON SALIVARY TACHYKININS . .232 SECRETION. .228 6.3. RECEPTORTRANSDUCTION 4.3. TACHYRININ RECEPTORS MECHANISMSOFTHESECRETORY ANDRECEPTORMECHANISMSIN ACTIONSOFTACHYRININS. .233 SALIVARYSECRETION. .228 *Correspondingauthor 220 P. Holzer and U. Holzer-Petsche 6.4. PHYSIOLOGICALIMPLICATIONS 10.1.OVERVIEW . .240 OFTACHYKININSININTESTINAL 10.2.PATHOLOGICALCHANGESIN SECRETION. .234 TACHYKININANDTACHYKININ 7. TACHYK~NINSANDHEPATOBILIARY RECEPTOREXPRESSION. .241 SECRETION . .235 10.2.1.CHANGES ASSOCIATED 7.1. OVERVIEW...............~~~ WITHGASTROINTESTINAL 7.2. ANTICHOLERETICEFFECTSOF DISEASEIN HUMANS. .241 TACHYKININS. .236 10.2.2.CHANGES ASSOCIATED 8. TACHYKININSANDPANCREATIC WITHEXPERIMENTAL SECRETION . .236 MODELSOF 8.1. OVERVIEW...............~~~ GASTROINTESTINAL 8.2.EFFECTSOFTACHYKININSON DISEASE . .241 EXOCRINEPANCREATIC 10.3.TACHYKININSIN SECRETION. .236 GASTROINTESTINALTUMORS . .243 8.3. EFFECTSOFTACHYI~NINS 10.4.PATHOPHYSIOLOGICAL ONENDOCRINEPANCREATIC IMPLICATIONSOFTACHYKININS IN SECRETION. , . .237 GASTROINTESTINAL SECRETION. .244 8.4. PHYSIOLOGICALIMPLICATIONS OF 10.4.1.SALIVARY SECRETION. .244 TACHYKININSINTHEPANCREAS. .237 10.4.2.INTESTINAL SECRETION. .244 9. TACHYK~NINSANDGASTROINTESTINAL 10.4.3.THERAPEUTIC CIRCULATION. , . .237 PROSPECTS. .244 9.1. OVERVIEW. .237 10.5. PATHOPHYSIOLOGICALROLESOF 9.2. VASODILATOREFFECTSOF TACHYKININSIN TACHYKININS. .237 GASTROINTESTINAL 9.2.1.EFFECTS ON MESENTERIC INFJ4MMATIONAND ARTERIALBLOODFLOW. .237 TISSUEINJURY . .245 9.2.2.EFFECTS ON 10.5.1.IMPLICATIONSOF GASTROINTESTINAL TACHYKININSINTHE BLOODFLOW.......... VASCULARCOMPONENTS 9.2.3.EFFECTSONBLOODFLOWIN OFINFLAMMATION . .245 THESALIVARYGLANDS . .238 10.5.2.IMPLICATIONSOF 9.3. VASOCONSTRICTOREFFECTSOF TACHYKININSINTHE TACHYKININS. .239 IMMUNOLOGICAL 9.4. EFFECTSOFTACHYKININSON COMPONENTSOF VASCULARPERMEABILITY . .239 INFLAMMATION . .245 9.5. F'I-IYSIOLOGICALROLESOF 10.5.3.TISSUEINJURYAND TACHYKININSINTHEVASCULAR PROTECTION. .246 SYSTEMOFTHEGUT . ..239 10.5.4.THERAPEUTIC 10. PATHOPHYSIOLOGICAL IMPLICATIONS PROSPECTS. .247 OFTACHYKININSINTHEGUTAND AcKNowLEDGEMENTs.............~~ 7 THERAPEUTICPERSPECTIVES. .240 REFERENCES ................. .247 ABBREVIATIONS. ACh, acetylcholine; CCK, cholecystokinin; CGRP, calcitonin gene-related peptide; EPSP, excitatory postsynaptic potential; GABA, y-aminobutyric acid; 5HT, 5hydroxytryptamine; Ig, immuno- globulin; I,,, short circuit current; MP, myenteric plexus; NANC, nonadrenergic noncholinergic; NK, neuroki- nin; NO, nitric oxide; NPK, neuropeptide K; PFT, preprotachykinin; SMP, submucosal plexus; SP, substance P; TTX, tetrodotoxin; TNBSA, trinitrobenzene sulphonic acid; VIP, vasoactive intestinal polypeptide. 1. INTRODUCTION of tachykinins are brought about by specific tachykinin re- The tachykinins are a family of small biologically active ceptors, of which three subtypes (NK,, NK2, NK3) have peptides whose principal mammalian members are sub- been identified and characterized by molecular pharmaco- stance P (SP), neurokinin (NK) A and NKB. These pep- logical techniques (Regoli et al., 1994; Maggi, 1995). tides are derived from precursor proteins, the preprotachy Ever since SP was discovered to occur in the intestine kinins (PPTs), which are encoded by two different PPT and to contract gastrointestinal smooth muscle (von Euler genes. PPT-A contains the sequences that encode both SP and Gaddum, 193 1 ), the implication of tachykinins in the and NKA, whereas the PPT-B encodes NKB only. As out- regulation of gastrointestinal motility has been the most ex- lined in the companion article (Holzer and Holzer-Petsche, tensively studied area of visceral tachykinin research. The 1997), SP and NKA abound in the digestive system, in expression, release, pharmacology and motor functions of which they are primarily expressed in intrinsic enteric and SP and NKA in the gut are reviewed in the companion ar- extrinsic primary afferent neurons. In view of their stimu- ticle (Holzer and Holzer-Petsche, 1997). Recent work, lus-induced release and predominant excitatory action on however, has provided novel information that extends the intestinal nerve and muscle, SP and NKA are thought to physiological and pathophysiological implications of tachy- play a neurotransmitter and/or neuromodulator role, and in kinins, signifying that these peptides may be important reg this way to regulate various digestive functions. The actions ulators of neural excitability, secretory processes and con- Tachykinins in Intestinal Secretion and Inflammation 221 tributory factors in certain secretory and inflammatory The quantitatively most significant source of mucosal SP disturbances of the gut. The present review attempts to dis- and NKA is provided by fibers that originate from the gan- cuss the distribution, actions and physiological roles of ta- glionated plexus of the enteric nervous system (Fig. 1). The chykinins in the mucosal, glandular and vascular systems of fibers of these neurons typically supply the lamina propria the gut in a comprehensive manner artd ,to review patho- and may run in immediate proximity to the epithelium of logical changes in these systems with a perspective for the human, equine, sheep, porcine, canine, marmoset, novel strategies in the therapy of secretory and inflamma- guinea-pig, rat and murine intestine (Costa et al., 1981; tory disorders. Llewellyn-Smith et al., 1984; Ekblad et al., 1985, 1987, 1988; Keast et al., 1985a; Wathuta, 1986; Daniel et al., 2. OCCURRENCE OF TACHYKININS IN THE 1987; Schmidt et al., 1991; Bums and Cummings, 1993; Ki- MUCOSAL, GLANDULAR AND VASCULAR tamura et al., 1993). SP-immunoreactive nerve fibers in the SYSTEMS OF THE GUT human duodenum come close to the acini of Brunner’s 2.1. Overview glands (Keast et al., 1985a; Bosshard et al., 1989). Whereas myenteric neurons are probably the only intrinsic neural The mammalian gastrointestinal tract contains both SP source of SP in the gastric mucosa of dogs and other species and NKA and
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