Die neurogene Entzündung.
II. Pathophysiologie und klinische Implikationen

Zusammenfassung

Neurogene Entzündungen werden hervorgerufen durch Aktivierung unmyelinisierter sensorischer Nervenfasern und nachfolgender Freisetzung von Neuropeptiden, z. B. Substanz P und Calcitonin Gene-related Peptide (CGRP) aus den peripheren Nervenendigungen. Die lokale Entzündungsreaktion am Ort der Reizung besteht aus einer Hyperämie und einem Ödem, die unter Umständen mit Schmerzen einhergehen. Die Entzündungszeichen und die Hyperalgesie bei chronischen Schmerzsyndromen, z. B. der Migräne, Arthritiden und dem Komplexen Regionalen Schmerzsyndrom entsprechen den Charakteristika der neurogenen Entzündung. Aufgrund überzeugender Hinweise aus Tierversuchen, die überwiegend an Nagern durchgeführt wurden, wird auch beim Menschen angenommen, dass die neurogene Entzündung an vielen Erkrankungen der Atemwege, des Magendarmtraktes, des Urogenitaltraktes und der Haut beteiligt sind. In Anbetracht der eher enttäuschenden Ergebnisse neuer klinischer Studien zur Behandlung neurogener Entzündungen mit selektiven Substanz P- (NK₁)-Antagonisten werden in dieser Übersicht die Hypothesen einer Beteiligung neurogener Entzündungen an Erkrankungen beim Menschen kritisch hinterfragt. Außer dem inflammatorischen Charakter hat die neurogene Entzündung in ganz anderer Weise physiologisch eine besondere Bedeutung. Sie hat eine protektive und nozifensive, aber auch trophische Funktion und trägt mit zur Gewebeintegrität und -homöostase bei.

Abstract

Neurogenic inflammation is elicited by activation of unmyelinated sensory neurons through noxious stimuli and subsequent release of neuropeptides such as substance P and calcitonin gene-related peptide (CGRP) from peripheral nerve endings. The nerve-mediated inflammatory responses in the tissue consist of hyperaemia and oedema which under some circumstances may be accompanied by pain. Neurogenic inflammation has been implicated in the pathophysiology of various human diseases with uncertain etiology. Signs of inflammation and hyperalgesia associated with chronic pain syndromes such as migraine, arthritis and complex regional pain syndrome resemble the characteristics of neurogenic inflammation. By extrapolation of convincing evidence obtained in rodent models, neurogenic inflammation is assumed to contribute to diseases of the respiratory system, gastrointestinal tract, urogenital tract, and skin in humans. Since, however, highly selective substance P receptor antagonists, found to be effective against inflammation in rodents, failed to inhibit inflammatory processes in clinical trials, the hypothesis of an involvement of neurogenic inflammation in human diseases is discussed critically in this review. Beyond its primarily inflammatory character neurogenic inflammation can be regarded as a mechanism that activates protective responses, thus bringing about a first line of defence to maintain the integrity of the tissue and to contribute to tissue repair.

Schlüsselwörter

Neurogene Entzündung - Pathophysiologie - Migräne - Arthritis

Keywords

Neurogenic inflammation - Pathophysiology - Migraine - Human diseases

Literatur

• 1 Holzer P. Local effector functions of capsaicin-sensitive sensory nerve endings: involvement of tachykinins, calcitonin gene-related peptide and other neuropeptides.  Neuroscience. 1988;  24 739-768
• 2 Holzer P. Peptidergic sensory neurons in the control of vascular functions: mechanisms and significance in the cutaneous and splanchnic vascular beds.  Rev Physiol Biochem Pharmacol. 1992;  121 49-146
• 3 Holzer P. Neurogenic vasodilatation and plasma leakage in the skin.  Gen Pharmac. 1998;  30 5-11
• 4 Herbert M K, Holzer P. Die neurogene Entzündung. I. Grundlegende Mechanismen, Physiologie und Pharmakologie. Anaesth Intensivmed Notfallmed Schmerzther (eingereicht)
• 5 Donnerer J, Amann R. The inhibition of neurogenic inflammation.  Gen Pharmacol. 1993;  24 519-529
• 6 Holzer P. Capsaicin: cellular targets, mechanisms of action, and selectivity for thin sensory neurons.  Pharmacol Rev. 1991;  43 143-201
• 7 Szallasi A, Blumberg P M. Vanilloid receptors: new insights enhance potential as a therapeutic target.  Pain. 1996;  68 195-208
• 8 Resnick D, Niwayama G. Entheses and enthesopathy.  Radiology. 1983;  146 1-9
• 9 Ball J. Enthesopathy of rheumatoid and ankylosing spondylitis.  Ann Rheum Dis. 1971;  30 213-223
• 10 Niepel G A, Sitaj S. Enthesopathy.  Clin Rheum Dis. 1979;  5 857-872
• 11 Ljung B O, Forsgren S, Friden J. Substance P and calcitonin gene-related peptide expression at the extensor carpi radialis brevis muscle origin: Implications for the etiology of tennis elbow.  J Orthop Res. 1999;  17 554-559
• 12 Haker E, Theodorsson E, Lundeberg T. An experimental model of tennis elbow in rats: A study of the contribution of the nervous system.  Inflammation. 1998;  22 435-444
• 13 Herbert M K, Tafler R, Schmidt R F, Weis K H. Cyclooxygenase inhibitors acetylsalicylic acid and indomethacin do not affect capsaicin-induced neurogenic inflammation in human skin.  Agents Actions. 1993;  38 C25-C27
• 14 Tafler R, Herbert M K, Schmidt R F, Weis K H. Small reduction of capsaicin-induced neurogenic inflammation in human forearm skin by the glucocorticoid prednicarbate.  Agents Actions. 1993;  38 31-34
• 15 Herbert M K. Neurogene Entzündung an Haut und Gelenk. Klinische und tierexperimentelle Studien. Habilitationsschrift, Julius-Maximilians-Universität Würzburg 1994
• 16 Ferrell W R, Russell N J. Extravasation in the knee induced by antidromic stimulation of articular C fibre afferents of the anaesthetized cat.  J Physiol Lond. 1986;  379 407-416
• 17 Malone D G, Irani A M, Schwartz L B, Barrett K E, Metcalfe D D. Mast cell numbers and histamine levels in synovial fluids from patients with diverse arthritides.  Arthritis Rheum. 1986;  29 956-963
• 18 Marshall K W, Chiu B, Inman R D. Substance P and arthritis: analysis of plasma and synovial fluid levels.  Arthritis Rheum. 1990;  33 87-90
• 19 Appelgren A, Appelgren B, Eriksson S, Kopp S, Lundeberg T, Nylander M, Theodorsson E. Neuropeptides in temporomandibular joints with rheumatoid arthritis: a clinical study.  Scand J Dent Res. 1991;  99 519-521
• 20 Marabini S, Matucci C erinic, Geppetti P, Del Bianco E, Marchesoni A, Tosi S, Cagnoni M, Partsch G. Substance P and somatostatin levels in rheumatoid arthritis, osteoarthritis, and psoriatic arthritis synovial fluid.  Ann N Y Acad Sci. 1991;  632 435-436
• 21 Joyce T J, Yood R A, Carraway R E. Quantitation of substance-P and its metabolites in plasma and synovial fluid from patients with arthritis.  J Clin Endocrinol Metab. 1993;  77 632-637
• 22 Anichini M, Cesaretti S, Lepori M, Maddali-Bongi S, Maresca M, Zoppi M. Substance P in the serum of patients with rheumatoid arthritis.  Rev Rhum Engl Ed. 1997;  64 18-21
• 23 Arnalich F, de Miguel E, Perez Ayala C, Martinez M, Vazquez J J, Gijon B anos, Hernanz A. Neuropeptides and interleukin-6 in human joint inflammation relationship between intraarticular substance P and interleukin-6 concentrations.  Neurosci Lett. 1994;  170 251-254
• 24 Courtright L J, Kuzell K C. Sparing effect of neurological deficit and trauma on the course of adjuvant arthritis in the rat.  Ann Rheum Dis. 1965;  24 360-368
• 25 Colpaert F C, Donnerer J, Lembeck F. Effects of capsaicin on inflammation and on the substance P content of nervous tissues in rats with adjuvant arthritis.  Life Sci. 1983;  32 1827-1834
• 26 Levine J D, Dardick S J, Roizen M F, Helms C, Basbaum A I. Contribution of sensory afferents and sympathetic efferents to joint injury in experimental arthritis.  J Neurosci. 1986;  6 3423-3429
• 27 Levine J D, Clark R, Devor M, Helms C, Moskowitz M A, Basbaum A I. Intraneuronal substance P contributes to the severity of experimental arthritis.  Science. 1984;  226 547-549
• 28 Levine J D, Moskowitz M A, Basbaum A I. The contribution of neurogenic inflammation in experimental arthritis.  J Immunol. 1985;  135 843s-847s
• 29 Basbaum A I, Levine J D. The contribution of the nervous system to inflammation and inflammatory disease.  Can J Physiol Pharmacol. 1991;  69 647-651
• 30 Donnerer J, Amann R, Lembeck F. Neurogenic and non-neurogenic inflammation in the rat paw following chemical sympathectomy.  Neuroscience. 1991;  45 761-765
• 31 Koltzenburg M, Kress M, Reeh P W. The nociceptor sensitization by bradykinin does not depend on sympathetic neurons.  Neuroscience. 1992;  46 465-473
• 32 Cambridge H, Brain S D. The role of sympathetic nerves in bradykinin (BK) induced plasma extravasation in the rat knee joint.  Can J Physiol Pharmacol. 1994;  72 (Suppl 2) 38-40
• 33 Donnerer J, Schuligoi R, Stein C. Increased content and transport of substance P and calcitonin gene-related peptide in sensory nerves innervating inflamed tissue: evidence for a regulatory function of nerve growth factor in vivo.  Neuroscience. 1992;  49 693-698
• 34 Kuraishi Y, Nanayama T, Ohno H, Fujii N, Otaka A, Yajima H, Satoh M. Calcitonin gene-related peptide increases in the dorsal root ganglia of adjuvant arthritic rat.  Peptides. 1989;  10 447-452
• 35 Marlier L, Poulat P, Rajaofetra N, Privat A. Modifications of serotonin-, substance P- and calcitonin gene-related peptide-like immunoreactivities in the dorsal horn of the spinal cord of arthritic rats: a quantitative immunocytochemical study.  Exp Brain Res. 1991;  85 482-490
• 36 Maleki J, LeBel A A, Bennett G J, Schwartzman R J. Patterns of spread of complex regional pain syndrome, type I (reflex sympathetic dystrophy).  Pain. 2000;  88 259-266
• 37 Pedersen-Bjergaard U, Nielsen L B, Jensen K, Edvinsson L, Jansen I, Olesen J. Calcitonin gene-related peptide, neurokinin A and substance P: effects on nociception and neurogenic inflammation in human skin and temporal muscle.  Peptides. 1991;  12 333-337
• 38 Wallengren J, Hakanson R. Effects of substance P, neurokinin A and calcitonin gene-related peptide in human skin and their involvement in sensory nerve-mediated responses.  Eur J Pharmacol. 1987;  143 267-273
• 39 Stewart J M, Getto C J, Neldner K, Reeve E B, Kirvoy W A, Zimmermann E. Substance P and analgesia.  Naunyn Schmiedeberg's Arch. Pharmacol.. 1976;  262 784-785
• 40 Kessler W, Kirchhoff C, Reeh P W, Handwerker H O. Excitation of cutaneous afferent nerve endings in vitro by a combination of inflammatory mediators and conditioning effect of substance P.  Exp Brain Res. 1992;  91 467-476
• 41 Herbert M K, Schmidt R F. Sensitization of articular afferents to mechanical stimuli by substance P.  Inflamm Res. 2001;  50 275-282
• 42 Culp W J, Ochoa J, Cline M, Dotson R. Heat and mechanical hyperalgesia induced by capsaicin. Cross modality threshold modulation in human C nociceptors.  Brain. 1989;  112 1317-1331
• 43 Cervero F, Gilbert R, Hammond R G, Tanner J. Development of secondary hyperalgesia following non-painful thermal stimulation of the skin: a psychophysical study in man.  Pain. 1993;  54 181-189
• 44 Kilo S, Schmelz M, Koltzenburg M, Handwerker H O. Different patterns of hyperalgesia induced by experimental inflammation in human skin.  Brain. 1994;  117 385-396
• 45 Coderre T J, Melzack R. Cutaneous hyperalgesia: contributions of the peripheral and central nervous systems to the increase in pain sensitivity after injury.  Brain Res. 1987;  404 95-106
• 46 Baumann T K, Simone D A, Shain C N, LaMotte R H. Neurogenic hyperalgesia: the search for the primary cutaneous afferent fibers that contribute to capsaicin-induced pain and hyperalgesia.  J Neurophysiol. 1991;  66 212-227
• 47 LaMotte R H, Shain C N, Simone D A, Tsai E F. Neurogenic hyperalgesia: psychophysical studies of underlying mechanisms.  J Neurophysiol. 1991;  66 190-211
• 48 LaMotte R H, Lundberg L E, Torebjörk H E. Pain, hyperalgesia and activity in nociceptive C units in humans after intradermal injection of capsaicin.  J Physiol Lond. 1992;  448 749-764
• 49 Simone D A, Sorkin L S, Oh U, Chung J M, Owens C, LaMotte R H, Willis W D. Neurogenic hyperalgesia: central neural correlates in responses of spinothalamic tract neurons.  J Neurophysiol. 1991;  66 228-246
• 50 Torebjörk H E, Lundberg L E, LaMotte R H. Central changes in processing of mechanoreceptive input in capsaicin-induced secondary hyperalgesia in humans.  J Physiol Lond. 1992;  448 765-780
• 51 Reeh P W, Kocher L, Jung S. Does neurogenic inflammation alter the sensitivity of unmyelinated nociceptors in the rat?.  Brain Res. 1986;  384 42-50
• 52 Meyer R A, Campbell J N, Raja S N. Antidromic nerve stimulation in monkey does not sensitize unmyelinated nociceptors to heat.  Brain Res. 1988;  441 168-172
• 53 Ray B S, Wolff H G. Experimentel studies on headache. Pain-sensitive structures of the head and their significance in headache.  Arch Surg. 1940;  41 813-856
• 54 Moskowitz M A, Lee W S, Cutrer F M. Sensory neuropeptides in migraine. Geppetti P, Holzer P (eds) Neurogenic inflammation. CRC Press, Boca Raton New York London Tokyo 1996: 187-199
• 55 Buzzi M G, Bonamini M, Moskowitz M A. Neurogenic model of migraine.  Cephalalgia. 1995;  15 277-280
• 56 May A, Shepheard S L, Knorr M, Effert R, Wessing A, Hargreaves R J, Goadsby P J, Hiener H C. Retinal plasma extravasation in animals but not in humans: implications for the pathophysiology of migraine.  Brain. 1998;  121 1231-1237
• 57 May A, Goadsby P J. Substance P receptor antagonists in the therapy of migraine.  Expert Opin Investig Drugs. 2001;  10 673-678
• 58 Escott K J, Beattie D T, Connor H E, Brain S D. Trigeminal ganglion stimulation increases facial skin blood flow in the rat: a major role for the calcitonin gene-related peptide.  Brain Res. 1995;  669 93-99
• 59 Messlinger K, Hanesch U, Kurosawa M, Pawlak M, Schmidt R F. Calcitonin gene related peptide released from dural nerve fibers mediates increase of meningeal blood flow in the rat.  Can J Physiol Pharmacol. 1995;  73 1020-1024
• 60 Feuerstein G, Wilette R, Aiyar N. Clinical perspectives of calcitonin gene related peptide pharmacology.  Can J Physiol Pharmacol. 1995;  73 1070-1074
• 61 O'Connor T P, van der Kooy D. Pattern of intracranial and extracranial projections of trigeminal ganglion cells.  J Neurosci. 1986;  6 2200-2207
• 62 Phebus L A, Johnson K W, Stengel P W, Lobb K L, Nixon J A, Hipskind P A. The non-peptide receptor antagonist LY 303870 inhibits neurogenic dural infalmmation in guinea pigs.  Life Sci. 1997;  60 1553-1561
• 63 Shepheard S L, Williamson D J, Hill R G, Hargreaves R J. The non-peptide neurokinin-1 receptor antagonist, RP 67580, blocks neurogenic plasma extravasation in the dura mater of rats.  Br J Pharmacol. 1993;  108 11-12
• 64 Lee W S, Moussaoui S M, Moskowitz M A. Oral or parenteral non-peptide NK₁ receptor antagonist RpR 100,893 blocks neurogenic plasma extravasation within guinea-pig dura mater and conjunctiva.  Br J Pharmacol. 1994;  112 920-924
• 65 Buzzi M G, Carter W B, Shimizu T, Heath H, Moskowitz M A. Dihydroergotamine and sumatriptan attenuate levels of CGRP in plasma in rat superior sagittal sinus during electrical stimulation of the trigeminal anglion.  Neuropharmacology. 1991;  30 1193-1200
• 66 Goadsby P J, Edvinsson L, Ekam R. Release of vasoactive peptides in the extracerebral circulation in humans and the cat during activation of the trigeminovascular system.  Ann Neurol. 1993;  23 193-196
• 67 Buzzi M G, Moskowitz M A. The antimigraine drug, sumatriptan (GR43175), selectively blocks neurogenic plasma extravasation from blood vessels in dura mater.  Br J Pharmacol. 1990;  99 202-206
• 68 Lee W S, Moskowitz M A. Conformationally restricted sumatriptan analogues, CP-122,288 and CP-122,638 exhibit enhanced potency against neurogenic inflammation in dura mater.  Brain Res. 1993;  626 303-305
• 69 Gupta P, Brown D, Butler P, Ellis P, Grayson K L, Land G C, Macor J E, Robson S F, Wythes M J, Shepperson N B. The in vivo pharmacological profile of a 5-HT1 receptor agonist, CP-122,288, a selective inhibitor of neurogenic inflammation.  Br J Pharmacol. 1995;  116 2385-2390
• 70 Cutrer F M, Moskowitz M A. Wolff Award 1996. The actions of valproate and neurosteroids in a model of trigeminal pain.  Headache. 1996;  36 579-585
• 71 Brändli P, Löffler B M, Breu V, Osterwalder R, Maire J P, Clozel M. Role of endothelin in mediating neurogenic plasma extravasation in rat dura mater.  Pain. 1995;  64 315-322
• 72 Ebersberger A, Schaible H G, Averbeck B, Richter F. Is there a correlation between spreading depression, neurogenic inflammation, and nociception that might cause migraine headache?.  Ann Neurol. 2001;  49 7-13
• 73 Lauritzen M. Pathophysiology of the migraine aura: the spreading depression theory.  Brain. 1994;  117 199-210
• 74 Olesen J, Larsen B, Lauritzen M. Focal hyperemia followed by spreading oligemia and impaired activation of rCBF in classic migraine.  Ann Neurol. 1981;  9 344-352
• 75 Leao A AP. Spreading depression of activity in the cerebral cortex.  J Neurophysiol. 1944;  7 359-390
• 76 Gardner-Medwin A R. Possible roles of vertebrate neuroglia in potassium dynamics, spreading depression and migraine.  J Exp Biol. 1981;  95 111-127
• 77 Moskowitz M A, Macfarlane R. Neurovascular and molecular mechanisms in migraine headaches.  Cerebrovasc Brain Metab Rev. 1993;  5 159-177
• 78 Roon K I, Olesen J, Diener H C, Ellis P, Hettiarachchi J, Poole P H, Christianssen I, Kleinermans D, Kok J G, Ferrari M D. No acute antimigraine effect of CP-122,288, a highly potent inhibitor of neurogenic inflammation: Results of two randomized, double-blind, placebo controlled clinical trials.  Ann Neurol. 2000;  47 238-241
• 79 Herbert M K, Holzer P. Warum versagen Substanz P (NK₁)-Rezeptoren in der Schmerztherapie?.  Anaesthesist. 2002;  51 308-319
• 80 Szolcsanyi J, Bartho L. Capsaicin-sensitive non-cholinergic excitatory innervation of the guinea-pig tracheobronchial smooth muscle.  Neurosci Lett. 1982;  34 247-251
• 81 Szolcsanyi J. Tetrodotoxin-resistant noncholinergic neurogenic contraction evoked by capsaicinoids and piperine on the guinea-pig trachea.  Neurosci Lett. 1983;  42 83-88
• 82 Lundberg J M, Saria A. Bronchial smooth muscle contraction induced by stimulation of capsaicin-sensitive sensory neurons.  Acta Physiol Scand. 1982;  116 473-476
• 83 Lundberg J M, Saria A. Capsaicin-induced desensitization of airway mucosa to cigarette smoke, mechanical and chemical irritants.  Nature. 1983;  302 251-253
• 84 Yamawaki I, Tamaoki J, Takeda Y, Nagai A. Inhaled cromoglycate reduces airway neurogenic inflammation via tachykinin antagonism.  Res Commun Mol Pathol Pharmacol. 1997;  98 265-272
• 85 Aizawa H, Koto H, Nakano H, Inoue H, Matsumoto K, Takata S, Shigyo M, Hara N. The effect of a specific tachykinin receptor antagonist FK-224 on ozone-induced airway hyperresponsiveness and inflammation.  Respirology. 1997;  2 261-265
• 86 Delay-Goyet P, Satoh H, Lundberg J M. Relative involvement of substance P and CGRP mechanisms in antidromic vasodilation in the rat skin.  Acta Physiol Scand. 1992;  146 537-538
• 87 Quartara L, Maggi C A. The tachykinin NK1 receptor. Part II: distribution and pathophysiological roles.  Neuropeptides. 1998;  32 1-49
• 88 Scheerens H, Buckley T L, Muis T, van Loveren H, Nijkamp F P. The involvement of sensory neuropeptides in toluene diisocyanate-induced tracheal hypereactivity in the mouse airways.  Br J Pharmacol. 1996;  119 1655-1671
• 89 Lundberg J M. Tachykinins, sensory nerves, and asthma - an overview.  Can J Physiol Pharmacol. 1995;  73 980-994
• 90 Barnes P J. Overview of neural mechanisms in asthma.  Pulm Pharmacol. 1995;  8 151-159
• 91 Barnes P J. Neuroeffector mechanisms: The interface between inflammation and neuronal responses.  J Allergy Clin Immunol. 1996;  98 S73-S83
• 92 Barnes P J. Neurogenic inflammation in the airways.  Respir Physiol. 2001;  125 145-154
• 93 Rumsey W L, Aharanoy D, Bialecki R A, Abbott B M, Barthlow H G, Caccese R, Ghanekar S, Lengel D, McCarthy M, Wenrich B, Undem B, Ohnmacht C, Shenvi A, Albert J S, Brown F, Bernstein P R, Russell K. Pharmacological characterization of ZD6021: A novel, orally active antagonist of the tachykinin receptors.  J Pharmacol Exp Ther. 2001;  298 307-315
• 94 Tampo T, Nabe T, Yasui K, Kamiki T, Kohno S. Participation of neuropeptides in antigen-induced contraction of guinea pig bronchi via NK₂ but not NK₁ receptor stimulation.  Pharmacology. 2000;  60 169-174
• 95 Lundblad L, Anggard A, Lundberg J M. Effects of antidromic trigeminal nerve stimulation in relation to parasympathetic vasodilatation in the cat nasal mucosa.  Acta Physiol Scand. 1983;  119 7-13
• 96 Asakura K, Shirasaki H, Narita S, Kojima T, Kautura A. Study on the dye leakage response of nasal mucosa following topical capsaicin challenge in guinea-pigs.  Acta Otolaryngol. 1992;  112 545-551
• 97 Petterson G, Malm L, Ekman R, Hakanson R. Capsaicin evokes secretion of nasal fliud and depletes substance P and CGRP from the nasal mucosa in the rat.  Br J Pharmacol. 1989;  98 930-936
• 98 Evangelista S, Paoli S, Giachetti A, Manzini S. Involvement of tachykinin NK₁ receptors in plasma protein extravasation induced by tachykinins in the guinea-pig upper airways.  Neuropeptides. 1997;  31 65-70
• 99 Geppetti P, Fusco B M, Marabini S, Maggi C A, Fanciullacci M, Sicuteri F. Secretion, pain and sneezing induced by application of capsaicin to the nasal mucosa in man.  Br J Pharmacol. 1988;  93 503-514
• 100 Philip G, Baroody F M, Proud D, Naclerio R M, Togias A G. The human nasal response to capsaicin.  J Allergy Clin Immunol. 1994;  94 1035-1045
• 101 Greiff L, Svensson C, Andersson M, Persson C G. Effects of topical capsaicin in seasonal allergic rhinitis.  Thorax. 1995;  50 225-229
• 102 Sanico A M, Satsuki A, Proud D, Togias A. Dose-dependent effects of capsaicin nasal challenge: In vivo evidence of human airway neurogenic inflammation.  J Allergy Clin Immunol. 1997;  100 632-641
• 103 Baraniuk J N, Lundgren J D, Okayama M, Merida M, Kaliner M A. Substance P and neurokinin A in human nasal mucosa.  Am J Resp Cell Mol Biol. 1991;  4 228-236
• 104 Joos G F, Kips J C, Peleman R A, Pauwels R A. Tachykinin antagonists and the airways.  Arch Int Pharmacodyn. 1995;  329 205-219
• 105 Rogers D F. Reflexly running noses: neurogenic inflammation in the nasal mucosa.  Clin Exp Allergy. 1996;  26 365-367
• 106 Baraniuk J N, Kaliner M. Neuropeptides and nasal secretion.  Am J Physiol. 1991;  261 L223-L235
• 107 Mantyh C R, Gates T S, Zimmerman R P, Welton M L, Passaro E P, Vigna S R, Magio J E, Kruger L, Mantyh P W. Receptor binding sites for substance P, but not substance K or neuromedin K, are expressed in high concentrations by arterioles, venules, and lymph nodules in surgical specimens obtained from patients with ulcerative colitis and Crohn disease.  Proc Natl Acad Sci USA. 1988;  85 3235-3239
• 108 Swain M G, Agro A, Blennerhassett P, Stanisz A, Collins S M. Increased levels of substance P in the myenteric plexus of trichinella-infected rats.  Gastroenterology. 1992;  102 1913-1919
• 109 Pothoulakis C, Castagliuolo I, LaMont J T, O'Keane J C, Snider R M, Leeman S E. CP-96,345, a substance P antagonist, inhibits rat intestinal responses to Clostridium difficile A but not cholera toxin.  Proc Natl Acad Sci USA. 1995;  91 947-951
• 110 McVey D C, Vigna S R. The capsaicin VR1 receptor mediates substance P release in toxin A-induced enteritis in rats.  Peptides. 2001;  22 1439-1446
• 111 Croci T, Landi M, Edmonds X, Le Furg G, Maffrand J P, Manara L. Role of tachykinins in castor oil induced diarrhea in rats.  Br J Pharmacol. 1997;  121 375-380
• 112 Stucchi A F, Shofer S, Leeman S, Materne O, Beer E, McClung A, Shebani K, Moore F, O'Brien M, Becker J M. NK-1 antagonist reduces colonic inflammation and oxidative stress in dextran sulfate-induced colitis in rats.  Am J Physiol Gastrointest Liver Physiol. 2000;  279 G1298-G1306
• 113 Sann H, Dux M, Schemann M, Jancso G. Neurogenic inflammation in the gastrointestinal tract of the rat.  Neurosci Lett. 1996;  219 147-130
• 114 Yiangou Y, Facer P, Dyer N HC, Chan C LH, Knowles C, Williams N S, Anand P. Vanilloid receptor 1 immunoreactivity in inflamed human bowel.  Lancet. 2001;  357 1338-1339
• 115 Sturiale S, Barbara G, Qiu B, Figini M, Geppetti P, Gerard N, Gerard C, Grady E F, Bunnett N W, Collins S M. Neutral endopeptidase (EC 3.4.24.11) terminates colitis by degrading substance P.  Proc Natl Acad Sci USA. 1999;  96 11653-11658
• 116 Talmage E K, Pouliot W A, Cornbrooks E B, Mawe G M. Transmitter diversity in ganglion cells of the guinea pig gallbladder: An immunohistochemical study.  J Comp Neurol. 1992 ;  317 45-56
• 117 Mawe G, Gershon M D. Structure, afferent innervation, and transmitter content of ganglia of the guinea pig gallbladder: Relationship to the enteric nervous system.  J Comp Neurol. 1989 ;  283 374-390
• 118 de Giorgio R, Zittel T T, Parodi J E, Becker J M, Brunicardi F C, Go V LW, Brecha N C, Sternini C. Peptide immunoreactivities in the ganglionated olexuses and nerve fibres innervating the human gallbladder.  J Auton Nerv Syst. 1995;  51 37-47
• 119 Jivegard L, Thornell E, Svanvik J. Fluid secretion by gallblader mucosa in experimental cholecystitis is influenced by intramural nerves.  Dig Dis Sci. 1987;  32 389-1394
• 120 Prystowsky J B, Rege R V. Neurogenic inflammation in cholecystitis.  Dig Dis Sci. 1997;  42 1489-1494
• 121 Maggi C A. The dual, sensory and „efferent” function of the capsaicin-sensitive primary sensory neurons in the urinary bladder and urethra. Maggi CA (ed) Nervous control of the urogenital system. Hardwood Publisher 1993: 383-422
• 122 Lecci A, Maggi C A. Tachykinins as modulators of the micturition reflex in the central and peripheral nervous system.  Regul Peptides. 2001;  101 1-18
• 123 Maggi C A, Patacchini R, Rovero P, Giachetti A. Tachykinin receptors and tachykinin receptor antagonists.  J Auton Pharmacol. 1993;  13 23-93
• 124 Ahluwalia A, Giuliani S, Scotland R, Maggi C A. Ovalbumin-induced neurogenic inflammation in the bladder of sensitized rats.  Br J Pharmacol. 1998;  124 190-196
• 125 de Ridder D, Chandiramani V, Dasgupta P, van Poppel H, Baert L, Fowler C J. Intravesical capsaicin as a treatment for refractory detrusor hyperreflexia: A dual center study with long-term followup.  J Urol. 1997;  158 2087-2092
• 126 Cruz F, Guimaraes M, Silva C, Rio M E, Coimbra A, Reis M. Desensitization of bladder sensory fibers by intravesical capsaicin has long lasting clinical and urodynamic effects on patients with hyperactive or hypersensitive bladder dysfunction.  J Urol. 1997;  157 585-589
• 127 Elbadawi A. Interstitial cystitis: a critique of current concepts with a new proposal for pathologic diagnosis and pathogenesis.  Urology. 1997;  49 (Suppl 5A) 14-40
• 128 Theoharides T C, Kempuraj D, Sant G R. Mast cell involvement in interstitial cystitis: a review of human and experimental evidence.  Urology. 2001;  57 (Suppl) 47-55
• 129 Wesselmann U. Neurogenic inflammation and chronic pelvic pain.  World J Urol. 2001;  19 180-185
• 130 Scholzen T, Armstrong C A, Bunnett N W, Luger T A, Olerud J E, Ansel J C. Neuropeptides in the skin: interactions between the neuroendocrine and skin immune systems.  Exp Dermatol. 1998;  7 81-96
• 131 Johansson O, Virtanen M, Hilliges M. Histaminergic nerves demonstrated in the skin. A new direct mode of neurogenic inflammation?.  Exp Dermatol. 1995;  4 93-96
• 132 Brzezinska-Blaszczyk E, Zalewska A. In vitro reactivity of mast cells in urticaria pigmentosa skin.  Arch Dermatol Res. 1998;  290 14-17
• 133 Brain S M. Sensory neuropeptides in the skin. Geppetti P, Holzer P (eds) Neurogenic inflammation. CRC Press, Boca Raton New York London Tokyo 1996: 229-244
• 134 Liang Y, Jacobi H H, Reimert C M, Haak-Frendscho M, Marcusson J A, Johansson O. CGRP-immunoreactive nerves in prurigo nodularis - an exploration of neurogenic inflammation.  J Cutan Pathol. 2000;  27 359-366
• 135 Rossi R, Johannson O. Cutaneous innervation and the role of neuronal peptides in cutaneous inflammation: a minireview.  Eur J Dermatol. 1998;  8 299-306
• 136 Maggi C A. Tachykinins and CGRP as co-transmitters released from peripheral endings of sensory nerves.  Prog Neurobiology. 1995;  45 1-98
• 137 Kjartansson J, Dalsgaard C J, Jonsson C E. Decreased survival of experimental critical flaps in rats after sensory denervation with capsaicin.  Plast Reconstr Surg. 1987;  79 218-221
• 138 Khalil Z, Helme R. Sensory peptides as neuromodulators of wound healing in aged rats.  J Gerontology. 1996;  51A B354-B361
• 139 Gherardini G, Gürlek A, Milner S M, Matarasso A, Evans G RD, Jernbeck J, Lundeberg . Calcitonin gene-related peptide improves skin flap survival and tissue inflammation.  Neuropeptides. 1998;  32 269-273
• 140 Németh J, Szilvássy Z, Thán M, Oroszi G, Sári R, Szolcsányi J. Decreased sensory neuropeptide release from trachea of rats with streptozotocin-induced diabetes.  Eur J Pharmacol. 1999;  369 221-224
• 141 Walmsley D, Wiles P G. Early loss of neurogenic inflammation in the human diabetic foot.  Clin Sci Colch. 1991;  80 605-610
• 142 Gyorfi A, Feazekas A, Feher E, Ender F, Rosivall L. Effects of streptocotozin-induced diabetes on neurogenic inflammation of gingivomusocal tissue in rat.  J Periodontal Res. 1996;  31 249-255
• 143 Forst T, Pfutzner A, Kunt T, Pohlmann T, Schenk U, Bauersachs R, Kustner E, Beyer J. Clin Sci.  Clin Sci. 1998;  94 255-261
• 144 Gamse R, Jancso G. Reduced neurogenic inflammation in streptozotocin-diabetic rats due to microvascular changes but not to substance P depletion.  Eur J Pharmacol. 1985;  118 175-180
• 145 Diemel L T, Stevens E J, Willars G B, Tomlinson D R. Depletion of substance P and calcitonin gene-related peptide in sciatic nerve of rats with experimental diabetes; effects of insulin and aldose reductase inhibition.  Neurosci Lett. 1992;  137 253-256
• 146 Németh J, Thán M, Sári R, Peitl B, Oroszi G, Farkas B, Szolcsányi J, Szilvássy Z. Impairment of neurogenic inflammation and anti-inflammatory responses in diabetic rats.  Eur J Pharmacol. 1999;  386 83-88
• 147 Ziche M. Sensory neuropeptides: mitogenic and trophic functions. Geppetti P, Holzer P (eds) Neurogenic inflammation. CRC Press, Boca Raton New York London Tokyo 1996: 253-263
• 148 Fan T P, Hu D E, Guard S, Gresham G A, Watling K J. Stimulation of angiogenesis by substance P and interleukin-1 in the rat and its inhibition by interleukin-1 or interleukin-1 receptor antagonists.  Br J Pharmacol. 1993;  110 43-49
• 149 Ziche M, Morbidelli L, Masini E, Amerini S, Granger H J, Maggi C A, Geppetti P, Ledda F. Nitric oxide mediates angiogenesis in vivo and endothelial cell growth and migration in vitro promoted by subtance P.  J Clin Invest. 1994;  94 2036-2044