Anästhesiol Intensivmed Notfallmed Schmerzther 2002; 37(6): 314-325
DOI: 10.1055/s-2002-32233
Übersicht
© Georg Thieme Verlag Stuttgart · New York

Die neurogene Entzündung

I. Grundlegende Mechanismen, Physiologie und PharmakologieNeurogenic InflammationI. Basic Mechanisms, Physiology and PharmacologyM.  K.  Herbert1 , P.  Holzer2
  • 1Klinik für Anaesthesiologie der Universität Würzburg
  • 2Institut für Exp. und Klin. Pharmakologie der Universität Graz, Österreich
Further Information

Publication History

Publication Date:
13 June 2002 (online)

Zusammenfassung

Die Aktivierung dünner sensorischer Nervenfasern durch noxische Reize bewirkt eine Freisetzung der Neuropeptide Substanz P und Calcitonin Gene-related Peptide, CGRP, aus den peripheren Nervenendigungen. Diese Neuropeptide und nachfolgend freigesetzte Mediatoren rufen am Ort der noxischen Reizung ein Ödem, eine Hyperämie und ferner ein Erythem hervor, dessen Ausdehnung über die Reizstelle hinausgeht (sog. flare response). Da diese Entzündungszeichen von der Funktion und Integrität peripherer sensorischer Neurone abhängen, wurde diese Reaktion neurogene Entzündung genannt. Da fast alle Gewebe von Säugern, inklusive dem Menschen, von afferenten nozizeptiven Neuronen innerviert sind, kann diese neurogene Entzündung überall im Körper auftreten. Obgleich seit mehr als einem Jahrhundert bekannt war, dass an dieser Reaktion, die mit antidromer Vasodilatation, Axonreflex, triple response, neurogener Entzündung beschrieben wurde, sensorische Afferenzen beteiligt sind, rückte die neurogene Entzündung erst in den vergangenen zwanzig Jahren als ein physiologisch und pathophysiologisch relevanter Prozess ins Bewusstsein. Eine Vielzahl endogener und exogener Substanzen können sensorische Nervenendigungen aktivieren und sensibilisieren und somit Schmerz oder eine nozizeptive Reaktion und eine neurogene Entzündung auslösen. Es wurde eine große Zahl pharmakologisch unterschiedlicher Substanzen und Mediatorantagonisten gefunden, die die neurogene Entzündung modulieren oder vermindern. Von besonderem Interesse sind hierbei Capsaicin und andere Agonisten und Antagonisten am Vanilloidrezeptor, da sie nozizeptive Neurone desensibilisieren und somit eine neurogene Entzündung vermindern oder gar verhindern können.

Abstract

Activation of sensory unmyelinated neurons by noxious stimuli evokes the release of neuropeptides, such as substance P and calcitonin gene-related peptide (CGRP) from peripheral nerve endings. These neuropeptides and subsequently released mediators cause a local oedema, hyperaemia and an erythema which extends beyond the site of stimulation (so-called flare response). Since these inflammatory signs depend on the function and integrity of peripheral sensory nervous systems, the response has been termed neurogenic inflammation. Due to the fact that nearly all tissues in mammals including humans are innervated by afferent sensory neurons, this neurogenic inflammation can occur ubiquitously throughout the body. Albeit first evidence showing that sensory neurons contribute to the inflammatory signs, described as antidromic vasodilatation, axon reflex, triple response, neurogenic inflammation, elicited at the level of tissue that they innervate was first obtained more than one hundred years ago, it was in the last two decades that inflammation caused by the release of neuropeptides from afferent nerve endings was recognised as a physiologically and pathologically relevant process. A large number of exogenous and endogenous substances and autacoids may stimulate or sensitise sensory nerve endings, thus simultaneously producing pain and nociceptive responses, as well as neurogenic inflammation. On the basis of recent research a variety of pharmacological substances and antagonists of putative mediators have been identified to modulate or suppress neurogenic inflammation, thus providing a rationale for therapeutical strategies for various diseases in which neurogenic inflammation is suggested to be involved. Among them, capsaicin and other newly developed agonists and antagonists at the vanilloid receptor have attracted particular attention, since they were found to be capable of desensitizing nociceptive nerve structures and thus of preventing development of neurogenic inflammation or even of abolishing an ongoing inflammatory process.

Literatur

  • 1 Perl E R. Mode of action of nociceptors. In: Hirsch C, Zotterman Y (eds) Cervical Pain. Pergamon, Oxford 1992: 157-164
  • 2 Burgess P R, Perl E R. Cutaneous mechanoreceptors and nociceptors. Iggo A (ed) Somatosensory System. Springer, Berlin 1973
  • 3 Lewis T. The Blood Vessels of the Human Skin and their Responses. Shaw and Sons, London 1927
  • 4 Lewis T. Experiments relating to cutaneous hyperalgesia and its spread through somatic nerves.  Clin Sci. 1936;  2 373-423
  • 5 Bruce N A. Über die Beziehung der sensiblen Nervenendigungen zum Entzündungsvorgang.  Arch exp Pathol Pharmakol. 1910;  63 424-433
  • 6 Jancsó N, Jancsó-Gabor A, Szolcsnyi J. Direct evidence for neurogenic inflammation and its prevention by denervation and pretreatment with capsaicin.  Br J Pharmacol Chemother. 1967;  31 138-151
  • 7 Stricker S. Untersuchungen über die Gefässwurzel des Ischiadicus.  Ber Akad Wiss Wien. 1876;  3 173-185
  • 8 Bayliss W M. On the origin from the spinal cord of vasodilator fibers of the hind limb, and on the nature of these fibers.  J Physiol Lond. 1901;  26 173-209
  • 9 Bruce N A. Vasodilator axon-reflexes.  Q J Exp Physiol. 1913;  6 339-354
  • 10 Breslauer F. Die Pathogenese der trophischen Gewebeschadens nach der Nervenverletzung.  Chir Deut Z. 1919;  150 50-81
  • 11 Jancsó N, Jancsó-Gabor A, Szolcsnyi J. The role of sensory nerve endings in neurogenic inflammation induced in human skin and in the eye and paw of the rat.  Br J Pharmacol Chemother. 1968;  32 32-41
  • 12 Willis W D. Exp Brain Res.  Dorsal root potentials and dorsal root reflexes: a double-edged sword. 1999;  124 395-421
  • 13 Lin Q, Wu J, Willis W D. Dorsal root reflexes and cutaneous neurogenic inflammation after intradermal injection of capsaicin in rats.  J Neurophysiol. 1999;  82 2602-2611
  • 14 Brimjoin S, Lundberg J M, Brodin E, Hökfelt T, Nilsson G. Axonal transport of substance P in the vagus and sciatic nerves of the guinea pig.  Brain Res. 1980;  191 443-448
  • 15 Gibson S J, Polak J M, Bloom S R, Sabate I M, Mulderry P M, Ghatei M A, McGregor G P, Morrison J F, Kelly J S, Evans R M. Calcitonin gene-related peptide immunoreactivity in the spinal cord of man and of eight other species.  J Neurosci. 1984;  4 3101-3111
  • 16 Moller K, Zhang Y Z, Hankanson R, Luts A, Sjolund B, Uddmann R, Sunder F. Pituitary adenylate cyclase activating peptide is a sensory neuropeptide: umminocytochemical and immunochemical evidence.  Neuroscience. 1993;  57 725-732
  • 17 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
  • 18 Rosenfeld M G, Mermod J J, Amara S G, Swanson L W, Sawchenko P E, Rivier J, Vale W W, Evans R M. Production of a novel neuropeptide encoded by the calcitonin gene via tissue-specific RNA processing.  Naunyn Schmiedeberg's Arch Pharmacol. 1983;  304 129-135
  • 19 Maggi C A, Patacchini R, Rovero P, Giachetti A. Tachykinin receptors and tachykinin receptor antagonists.  J Auton Pharmacol. 1993;  13 23-93
  • 20 Otsuka M, Yoshioka K. Neurotransmitter functions of mammalian tachykinins.  Physiol Rev. 1993;  73 229-308
  • 21 Ogawa T, Kanazawa I, Kimura S. Regional distribution of substance P, neurokinin alpha and neurokinin beta in rat spinal cord, nerve roots and dorsal root ganglia, and the effects of dorsal root section or spinal transection.  Brain Res. 1985;  359 152-157
  • 22 Hunt S P, Rossi J. Peptide- and non-peptide-containing unmyelinated primary afferents: the parallel processing of nociceptive information.  Philos Trans R Soc Lond Biol. 1985;  308 283-289
  • 23 Liu-Chen L Y, Liszczak T M, King J C, Moskowitz M A. Immunoelectron microscopic study of substance P-containing fibers in feline cerebral arteries.  Brain Res. 1986;  369 12-20
  • 24 Alvarez F J, Cervantes C, Blasco I, Villalba R, Martinez M urillo, Polak J M, Rodrigo J. Presence of calcitonin gene-related peptide (CGRP) and substance P (SP) immunoreactivity in intraepidermal free nerve endings of cat skin.  Brain Res. 1988;  442 391-395
  • 25 McNeill D L, Coggeshall R E, Carlton S M. A light and electron microscopic study of calcitonin gene-related peptide in the spinal cord of the rat.  Exp Neurol. 1988;  99 699-708
  • 26 Wiesenfeld-Hallin Z, Hokfelt T, Lundberg J M, Forssmann W G, Reinecke M, Tschopp F A, Fischer J A. Immunoreactive calcitonin gene-related peptide and substance P coexist in sensory neurons to the spinal cord and interact in spinal behavioral responses of the rat.  Neurosci Lett. 1984;  52 199-204
  • 27 Lee Y, Kawai Y, Shiosaka S, Takami K, Kiyama H, Hillyard C J, Girgis S, MacIntyre I, Emson P C, Tohyama M. Coexistence of calcitonin gene-related peptide and substance P-like peptide in single cells of the trigeminal ganglion of the rat: immunohistochemical analysis.  Brain Res. 1985;  330 194-196
  • 28 Gibbins I L, Furness J B, Costa M, MacIntyre I, Hillyard C J, Girgis S. Co-localization of calcitonin gene-related peptide-like immunoreactivity with substance P in cutaneous, vascular and visceral sensory neurons of guinea pigs.  Neurosci Lett. 1985;  57 125-130
  • 29 Gibbins I L, Wattchow D, Coventry B. Two immunohistochemically identified populations of calcitonin gene-related peptide (CGRP)-immunoreactive axons in human skin.  Brain Res. 1987;  414 143-148
  • 30 Cameron A A, Leah J D, Snow P J. The coexistence of neuropeptides in feline sensory neurons.  Neuroscience. 1988;  27 969-979
  • 31 Benrath J, Eschenfelder C, Zimmermann M, Gillardon F. Calcitonin gene-related peptide, substance P and nitric oxide are involved in cutaneous inflammation following ultraviolet irradiation.  Eur J Pharmacol Environ Toxicol Pharmacol Section. 1995;  293 87-96
  • 32 Maggi C A, Abelli L, Giuliani S, Santicioli P, Geppetti P, Somma V, Frilli S, Meli A. The contribution of sensory nerves to xylene-induced cystitis in rats.  Neuroscience. 1988;  26 709-723
  • 33 Low A, Westerman R A. Neurogenic vasodilation in the rat hairy skin measured using a laser Doppler flowmeter.  Life Sci. 1989;  45 49-57
  • 34 Koltzenburg M, Lewin G, McMahon S. Increase of blood flow in skin and spinal cord following activation of small diameter primary afferents.  Brain Res. 1990;  509 145-149
  • 35 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
  • 36 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
  • 37 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
  • 38 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
  • 39 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
  • 40 Towler P K, Bennett G S, Noore P H, Brain S D. Neurogenic oedema and vasodilatation: effect of a selective neuronal NO inhibitor.  Neuroreport. 1998;  9 1513-1518
  • 41 Sauerstein K, Klede M, Hilliges , Schmelz M. Electrically evoked neuropeptide release and neurogenic inflammation differ between rat and human skin.  J Physiol (Lond). 2000;  529 803-810
  • 42 Schmelz M, Petersen L J. Neurogenic inflammation in human and rodent skin.  News Physiol Sci. 2001;  16 33-37
  • 43 Lembeck F. Zur Frage der zentralen Übertragung afferenter Impulse-III. Mitteilung. Das Vorkommen und die Bedeutung der Substanz P in den dorsalen Wurzeln des Rückenmarks.  Arch exp Pathol Pharmakol. 1953;  219 197-213
  • 44 Chahl L A. Antidromic vasodilatation and neurogenic inflammation.  Pharmac Ther. 1988;  37 275-300
  • 45 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
  • 46 Bolton T B, Clapp L H. Endothelial-dependent relaxant actions of carbachol and substance P in arterial smooth muscle.  Br J Pharmacol. 1986;  87 713-723
  • 47 Burnstock G. Local mechanisms of blood flow control by perivascular nerves and endothelium.  J Hypertens Suppl. 1990;  8 S95-106
  • 48 Lembeck F, Holzer P. Substance P as neurogenic mediator of antidromic vasodilation and neurogenic plasma extravasation.  Naunyn Schmiedeberg's Arch Pharmacol. 1979;  310 175-183
  • 49 Pernow B. Substance P - a putative mediator of antidromic vasodilation.  Gen Pharmacol. 1983;  14 13-16
  • 50 Wiesner-Menzel L, Schulz B, Vakilzadeh F, Czarnetzki B M. Electron microscopical evidence for a direct contact between nerve fibres and mast cells.  Acta Derm Venereol Stockh. 1981;  61 465-469
  • 51 Newson B, Dahlstrom A, Enerback L, Ahlman H. Suggestive evidence for a direct innervation of mucosal mast cells.  Neuroscience. 1983;  10 565-570
  • 52 Tausk F, Undem B. Exogenous but not endogenous substance P releases histamine from isolated human skin fragments.  Neuropeptides. 1995;  29 351-355
  • 53 Rosenfeld M G, Mermod J J, Amara S G, Swanson L W, Sawchenko P E, Rivier J, Vale W W, Evans R M. Production of a novel neuropeptide encoded by the calcitonin gene via tissue-specific RNA processing.  Naunyn Schmiedeberg's Arch.Pharmacol.. 1983;  304 129-135
  • 54 Björklund H, Dalsgaard C J, Jonsson C E, Hermansson A. Sensory and autonomic innervation of non-hairy and hairy human skin. An immunohistochemical study.  Cell Tissue Res. 1986;  243 51-57
  • 55 Ishida Y amamoto, Senba E, Tohyama M. Distribution and fine structure of calcitonin gene-related peptide-like immunoreactive nerve fibers in the rat skin.  Brain Res. 1989;  491 93-101
  • 56 Jansen I, Uddman R, Hocherman M, Ekman R, Jensen K, Olesen J, Stiernholm P, Edvinsson L. Localization and effects of neuropeptide Y, vasoactive intestinal polypeptide, substance P, and calcitonin gene-related peptide in human temporal arteries.  Ann Neurol. 1986;  20 496-501
  • 57 Uddman R, Edvinsson L, Ekblad E, Hakanson R, Sundler F. Calcitonin gene-related peptide (CGRP): perivascular distribution and vasodilatory effects.  Regul Pept. 9186;  15 1-23
  • 58 Bjurholm A, Kreicbergs A, Brodin E, Schultzberg M. Substance P- and CGRP-immunoreactive nerves in bone.  Peptides. 1988;  9 165-171
  • 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 Uddman R, Edvinsson L, Jansen I, Stiernholm P, Jensen K, Olesen J, Sundler F. Peptide-containing nerve fibres in human extracranial tissue: a morphological basis for neuropeptide involvement in extracranial pain?.  Pain. 1986;  27 391-399
  • 61 Poyner D R. Calcitonin gene-related peptide: multiple actions, multiple receptors.  Pharmacol Ther. 1992;  56 23-51
  • 62 Brain S D, Williams T J, Tippins J R, Morris H R, MacIntyre I. Calcitonin gene-related peptide is a potent vasodilator.  Nature. 1985;  313 54-56
  • 63 Brain S D, Tippins J R, Morris H R, MacIntyre I, Williams T J. Potent vasodilator activity of calcitonin gene-related peptide in human skin.  J Invest Dermatol. 1986;  87 533-536
  • 64 Öhlen A, Lindbom L, Staines W, Hokfelt T, Cuello A C, Fischer J A, Hedqvist P. Substance P and calcitonin gene-related peptide: immunohistochemical localisation and microvascular effects in rabbit skeletal muscle.  Naunyn Schmiedebergs Arch Pharmacol. 1987;  336 87-93
  • 65 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
  • 66 Fuller R W, Conradson T B, Dixon C M, Crossman D C, Barnes P J. Sensory neuropeptide effects in human skin.  Br J Pharmacol. 1987;  92 781-788
  • 67 Piotrowski W, Foreman J C. Some effects of calcitonin gene-related peptide in human skin and on histamine release.  Br J Dermatol. 1986;  114 37-46
  • 68 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
  • 69 Ralevic V, Khalil Z, Dusting G J, Helme R D. Nitric oxide and sensory nerves are involved in the vasodilator response to acetylcholine but not calcitonin gene-related peptide in rat skin microvasculature.  Br J Pharmacol. 1992;  106 650-655
  • 70 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
  • 71 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
  • 72 Holzer P. Neurogenic vasodilatation and plasma leakage in the skin.  Gen Pharmac. 1988;  30 5-11
  • 73 Brain S D, Williams T J. Substance P regulates the vasodilator activity of calcitonin gene-related peptide.  Naunyn Schmiedeberg's Arch Pharmacol. 1988;  335 73-75
  • 74 Petersen L J, Winge K, Brodin E, Skov P S. No release of histamine and substance P in capsaicin-induced neurogenic inflammation in intact human skin in vivo: a microdialysis study.  Clin Exp Allergy. 1997;  27 957-965
  • 75 Schmelz M, Luz O, Averbeck B, Bickel A. Plasma extravasation and neuropeptide release in human skin as measured by intradermal microdialysis.  Neurosci Lett. 1997;  18 117-120
  • 76 Green B G. Temporal characteristics of capsaicin sensitization and desensitization on the tongue.  Physiol Behav. 1991;  49 501-505
  • 77 Szolcsanyi J, Bartho L. Capsaicin-sensitive non-cholinergic excitatory innervation of the guinea-pig tracheobronchial smooth muscle.  Neurosci Lett. 1982;  34 247-251
  • 78 Bergren D R. Capsaicin challenge, reflex bronchoconstriction, and local action of substance P.  Am J Physiol. 1988;  254 R845-852
  • 79 Palecek F, Sant'Ambrogio G, Sant'Ambrogio F B, Mathew O P. Reflex responses to capsaicin: intravenous, aerosol, and intratracheal administration.  J Appl Physiol. 1989;  67 1428-1437
  • 80 Belmonte C, Gallar J, Pozo M A, Rebollo I. Excitation by irritant chemical substances of sensory afferent units in the cat's cornea.  J Physiol (Lond). 1991;  437 709-725
  • 81 Holzer P. Capsaicin: cellular targets, mechanisms of action, and selectivity for thin sensory neurons.  Pharmacol Rev. 1991;  43 143-201
  • 82 Szolcsanyi J, Bartho L. New type of nerve-mediated cholinergic contractions of the guinea-pig small intestine and its selective blockade by capsaicin.  Naunyn Schmiedeberg's Arch Pharmacol. 1978;  305 83-90
  • 83 Nagy J I, Iversen L L, Goedert M, Chapman D, Hunt S P. Dose-dependent effects of capsaicin on primary sensory neurons in the neonatal rat.  J Neurosci. 1983;  3 399-406
  • 84 Buck S H, Burks T F. The neuropharmacology of capsaicin: review of some recent observations.  Pharmacol Rev. 1986;  38 179-226
  • 85 Lawson S N, Harper A A. Neonatal capsaicin is not a specific neurotoxin for sensory C-fibres or small dark cells of rat dorsal root ganglia. Chahl LA, Szolcsnyi J, Lembeck F (eds) Antidromic Vasodilatation and Neurogenic Inflammation. Akadémiai Kiadó, Budapest 1984: 111-116
  • 86 Jancsó G, Kiraly E, Joo F, Such G, Nagy A. Selective degeneration by capsaicin of a subpopulation of primary sensory neurons in the adult rat.  Neurosci Lett. 1985;  59 209-214
  • 87 Fitzgerald M, Woolf C J. The time course and specificity of the changes in the behavioural and dorsal horn cell responses to noxious stimuli following peripheral nerve capsaicin treatment in the rat.  Neuroscience. 1982;  7 2051-2056
  • 88 Green B G, Shaffer G S. The sensory response to capsaicin during repeated topical exposures: differential effects on sensations of itching and pungency.  Pain. 1993;  53 323-334
  • 89 Maggi C A, Meli A. The sensory-efferent function of capsaicin-sensitive sensory neurons.  Gen Pharmacol. 1988;  19 1-43
  • 90 Crimi N, Polosa R, Maccarrone C, Palermo B, Palermo F, Mistretta A. Effect of topical application with capsaicin on skin responses to bradykinin and histamine in man.  Clin Exp Allergy. 1992;  22 933-939
  • 91 DeVries D J, Blumberg P M. Thermoregulatory effects of resiniferatoxin in the mouse: comparison with capsaicin.  Life Sci. 1989;  44 711-715
  • 92 Szallasi A, Blumberg P M. Vanilloid receptors: new insights enhance potential as a therapeutic target.  Pain. 1996;  68 195-208
  • 93 Szallasi A, Blumberg P M. Resiniferatoxin and analogs provide novel insights into the pharmacology of the vanilloid (capsaicin) receptor.  Life Sci. 1990;  47 1399-1408
  • 94 Szallasi A. The vanilloid receptor. Geppetti P, Holzer P (eds) Neurogenic inflammation. CRC Press, Boca Raton New York London Tokyo 1996: 43-52
  • 95 Szolcsanyi J, Szallasi A, Szallasi Z, Joo F, Blumberg P M. Resiniferatoxin, an ultrapotent selective modulator of capsaicin-sensitive primary afferent neurons.  J Pharmacol Exp Ther. 1990;  255 923-927
  • 96 Bevan S, Hothi S, Hughes G, James I F, Rang H P, Shah K, Walpole C SJ, Yeats J C. Capsazepine: a competitive antagonist of the sensory neurone excitant capsaicin.  Br J Pharmacol. 1992;  107 544-552
  • 97 Szallasi A. The vanilloid (capsaicin) receptor: receptor types and species differences.  Gen Pharmacol. 1994;  25 223-243
  • 98 Perkins M N, Campbell E A. Capsazepine reversal of the antinociceptive action of capsaicin in vivo.  Br J Pharmacol. 1992;  107 329-333
  • 99 Urban L, Dray A. Capsazepine, a novel capsaicin antagonist, selectively antagonises the effects of capsaicin in the mouse spinal cord in vitro.  Neurosci Lett. 1991;  134 9-11
  • 100 Lalloo U G, Fox A J, Belvisi M G, Chung K F, Barnes P J. Capsazepine inhibits cough induced by capsaicin and citric acid but not by hypertonic saline in guinea pigs.  J Appl Physiol. 1995;  79 1082-1087
  • 101 Santos A RS, Calixto J B. Ruthenium red and capsazepine aninociceptive effect in formalin and capsaicin midels of pain in mice.  Neurosci Lett. 1997;  235 73-76
  • 102 Dickenson A, Hughes C, Rueff A, Dray A. A spinal mechanism of action is involved in the antinociception produced by the capsaicin analogue NE 19550 (olvanil).  Pain. 1990;  43 353-362
  • 103 Davis K D, Meyer R A, Turnquist J L, Filloon T G, Pappagallo M, Campbell J N. Cutaneous pretreatment with the capsaicin analog NE-21610 prevents the pain to a burn and subsequent hyperalgesia.  Pain. 1995;  62 373-378
  • 104 Hua X Y, Chen P, Hwang J H, Yaksh T L. Antinociception induced by civamide, an orally active capsaicin analogue.  Pain. 1997;  71 313-322
  • 105 Szallasi A, Blumberg P M, Nilsson S, Hökfelt T, Lundberg J M. Visualization by [3H]resiniferatoxin autoradiography of capsaicin-sensitive neurons in the rat, pig, and man.  Eur J Pharmacol. 1994;  264 217-224
  • 106 Szallasi A, Goso C. Characterization by [3H]resiniferatoxin binding of a human vanilloid (capsaicin) receptor in post-mortem spinal cord.  Neurosci Lett. 1994;  165 101-104
  • 107 Caterina M J, Schumacher M A, Tominaga M, Rosen T A, Levine J D, Julius D. The capsaicin receptor: a heat activated ion channel in the pain pathway.  Nature. 1997;  389 816-824
  • 108 Wood J N, Winter J, James I F, Rang H P, Yeats J, Bevan S. Capsaicin-induced ion fluxes in dorsal root ganglion cells in culture.  J Neurosci. 1988;  8 3208-3220
  • 109 Bevan S, Geppetti P. Protons: small stimulants of capsaicin sensitive sensory nerves.  Trends Neurosci . 1994;  17 509-512
  • 110 Petersen M, LaMotte R H. Effect of protons on the inward current evoked by capsaicin in isolated dorsal root ganglion cells.  Pain. 1993;  54 37-42
  • 111 Kress M, Fetzer S, Reeh P, Vyklicky L. Low pH facilitates capsaicin responses in isolated sensory neurones of the rat.  Neurosci Lett. 1996;  211 5-8
  • 112 Jung J, Hwang S W, Kwak J, Lee S Y, Kang C J, Kim W B, Kim D, Oh U. Capsaicin binds to the intracellular domain of the capsaicin-activated ion channel.  J Neurosci. 1999;  19 529-538
  • 113 Olah Z, Karai L, Iadarola M J. Anandamide activates vanilloid receptor 1 (VR1) at acidic ph in dorsal root ganglia neurons and cells ectopically expressing VR1.  J Biol Chem. 201;  276 31163-31170
  • 114 Sprague J, Harrison C, Rowbotham D J, Smart D, Lambert D G. Temperature-dependent activation of recombinant rat vanilloid VR1 receptors expressed in HEK293 cells by capsaicin and anandamide.  Eur J Pharmacol. 2001;  423 121-125
  • 115 Szallasi A, DiMarzo V. New perspectives on enigmatic vanilloid receptors.  Trends Neurosci. 2000;  23 491-497
  • 116 Smart D, Gunthorpe M J, Jerman J C, Nasir S, Gray J, Muir A I, Chambers J K, Randall A D, Davis J B. The endogenous lipid anandamide is a full agonist at the human vailloid receptor (hVR1).  Br J Pharmacol. 2000;  129 227-230
  • 117 Vellani V, Mapplebeck S, Moriondo A, Davis J B, McNaughton P A. Protein kinase C activation potentiates gating of the vanilloid receptor VR1 by capsaicin, protons, heat and anandamide.  J Physiol (Lond). 2001;  534 813-825
  • 118 Watson C P, Evans R J. The postmastectomy pain syndrome and topical capsaicin: a randomized trial.  Pain. 1992;  51 375-379
  • 119 Watson C P, Evans R J, Watt V R. The post-mastectomy pain syndrome and the effect of topical capsaicin.  Pain. 1989;  38 177-186
  • 120 Rains C, Bryson H M. Topical capsaicin. A review of its pharmacological properties and therapeutic potential in post-herpetic neuralgia, diabetic neuropathy and osteoarthritis.  Drugs Aging. 1995;  7 317-328
  • 121 Puig L, Alegre M, de Moragas J M. Treatment of meralgia paraesthetica with topical capsaicin.  Dermatology. 1995;  191 73-74
  • 122 Low P A, Opfer-Gehrking T L, Dyck P J, Litchy W J, O'Brien P C. Double-blind, placebo-controlled study of the application of capsaicin cream in chronic distal painful neuropathy.  Pain. 1995;  62 163-168
  • 123 Quartara L, Maggi C A. The tachykinin NK1 receptor. Part I: ligands and mechanisms of cellular activation.  Neuropeptides. 1997;  31 537-563
  • 124 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
  • 125 Lowe J AIII, Snider R M, MacLean D B. Nonpeptide NK1 antagonists: from discovery to the clinic. In: Geppetti P, Holzer P (eds) Neurogenic inflammation.  CRC Press, Boca Raton New York London Tokyo 1996: 299-309
  • 126 Maggi C A. The pharmacology of the efferent function of sensory nerves.  J Auton Pharmacol. 1991;  11 173-208
  • 127 Maggi C A. Tachykinins as peripheral modulators of primary afferent nerves and visceral sensitivity.  Pharmacol Res. 1997;  36 153-169
  • 128 Quartara L, Maggi C A. The tachykinin NK1 receptor. Part II: distribution and pathophysiological roles.  Neuropeptides. 1998;  32 1-49
  • 129 Herbert M K, Holzer P. Warum versagen Substanz P (NK1)-Rezeptorantagonisten in der Schmerztherapie?.  Anaesthesist. 2002;  51 308-319
  • 130 Joos G F, Kips J C, Peleman R A, Pauwels R A. Tachykinin antagonists and the airways.  Arch Int Pharmacodyn. 1995;  329 205-219
  • 131 Barnes P J, Belvisi M G, Rogers D F. Modulation of neurogenic inflammation: novel approaches to inflammatory disease.  Trends Pharmacol Sci. 1990;  11 185-189
  • 132 Donnerer J, Amann R. The inhibition of neurogenic inflammation.  Gen Pharmacol. 1993;  24 519-529
  • 133 Lundberg J M, Saria A. Polypeptide-containing neurons in airway smooth muscle.  Annu Rev Physiol. 1987;  49 557-572
  • 134 Lembeck F. The 1988 Ulf Euler Lecture. Substance P: from extract to excitement.  Acta Physiol Scand. 1988;  133 435-454
  • 135 Lei Y H, Barnes P J, Rogers D F. Inhibition of neurogenic plasma exudation in guinea-pig airways by CP-96,345, a new non-peptide NK1 receptor antagonist.  Br J Pharmacol. 1992;  105 261-262
  • 136 Lembeck F, Donnerer J, Tsuchiya M, Nagahisa A. The non-peptide tachykinin antagonist, CP-96,345, is a potent inhibitor of neurogenic inflammation.  Br J Pharmacol. 1992;  105 527-530
  • 137 Szolcsanyi J, Heyles Z, Oroszi G, Nemeth J, Pinter E. Release of somatostatin and ist role in the mediation of the anti-inflammatory effect induced by antidromic stimulation of sensory fibres of rat sciatic nerve.  Br J Pharmacol. 1998;  123 936-942
  • 138 Pinter E, Szolcsanyi J. Systemic anti-inflammatory effect induced by antidromic stimulation of the dorsal roots in the rat.  Neurosci Lett. 1996;  212 33-36
  • 139 Herbert M K. Neurogene Entzündung an Haut und Gelenk. Klinische und tierexperimentelle Studien. Habilitationsschrift, Julius-Maximilians-Universität Würzburg 1994
  • 140 Ohkubo T, Shibata M, Inoue M, Kaya H, Takahashi H. Regulation of substance P release mediated by prejunctional histamine H3 receptors.  Eur J Pharmacol. 1995;  273 83-88
  • 141 Dux M, Janso G, Sann H, Pierau F K. Inhibition of the neurogenic inflammatory response by lidocaine in rat skin.  Inflamm Res. 1996;  45 10-13
  • 142 Lundberg J M, Saria A. Capsaicin-induced desensitization of airway mucosa to cigarette smoke, mechanical and chemical irritants.  Nature. 1983;  302 251-253
  • 143 Floreani A A, Rennard S I. Experimental treatments for asthma.  Curr Opin Pulm Med. 1997;  3 30-41
  • 144 Feletou M, Lonchampt M, Robineau P, Jamonneau I, Thurieau C, Fauchere J L, Villa P, Ghezzi P, Prost J F, Canet E. Effects of the bradykinin B2 receptor antagonist S16118 (p-guanidobenzoyl-[Hyp3,Thi5,D-Tic7,Oic8]bradykinin) in different in vivo animal models of inflammation.  J Pharmacol Exp Ther. 1995;  273 1078-1084
  • 145 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
  • 146 Buzzi M G, Moskowitz M A, Peroutka S J, Byun B. Further characterization of the putative 5-HT receptor which mediates blockade of neurogenic plasma extravasation in rat dura mater.  Br J Pharmacol. 1991;  103 1421-1428
  • 147 Matsubara T, Moskowitz M A, Byun B. CP-93,129, a potent and selective 5-HT1B receptor agonist blocks neurogenic plasma extravasation within rat but not guinea-pig dura mater.  Br J Pharmacol. 1991;  104 3-4
  • 148 Kajekar R, Gupta P, Shepperson N M, Brain S D. Effect of a 5-HT1 receptor agonist, CP-122,288, on oedema formation induced by stimulation of the rat saphenous nerve.  Br J Pharmacol. 1995;  115 1-2
  • 149 Pierce P A, Xie G X, Peroutka S J, Levine J D. Dual effects of the serotonin agonist, sumatriptan, on peripheral neurogenic inflammation.  Reg Anesth. 1996;  21 219-225
  • 150 Buzzi M G, Sakas D E, Moskowitz M A. Indomethacin and acetylsalicylic acid block neurogenic plasma protein extravasation in rat dura mater.  Eur J Pharmacol. 1989;  165 251-258
  • 151 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
  • 152 Stein C. Peripheral mechanisms of opioid analgesia.  Anesth Analg. 1993;  76 182-191
  • 153 Donnerer J, Amann R. Sensory pharmacology.  Pharmacol Toxicol. 1991;  69 228-232
  • 154 Bartho L, Stein C, Herz A. Involvement of capsaicin-sensitive neurones in hyperalgesia and enhanced opioid antinociception in inflammation.  Naunyn Schmiedebergs Arch Pharmacol. 1990;  342 666-670
  • 155 Helyes Z, Nemeth J, Pinter E, Szolcsanyi J. Inhibition by nociceptin of neurogenic inflammation and the release of SP and CGRP from sensory nerve terminals.  Br J Pharmacol. 1997;  121 613-615
  • 156 Brokaw J J, White G W. Characterization of ruthenium red as an inhibitor of neurogenic inflammation in the rat trachea.  Gen Pharmacacol. 1995;  26 327-331
  • 157 Amann R, Donnerer J, Lembeck F. Capsaicin-induced stimulation of polymodal nociceptors is antagonized by ruthenium red independently of extracellular calcium.  Neuroscience. 1989;  32 255-259
  • 158 Amann R, Donnerer J, Lembeck F. Activation of primary afferent neurons by thermal stimulation. Influence of ruthenium red.  Naunyn Schmiedeberg's Arch Pharmacol. 1990;  341 108-113
  • 159 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
  • 160 Bar-Shavit Z, Goldman R, Stabinsky Y, Gottlieb P, Fridkin M, Teichberg V I, Blumberg S. Enhancement of phagocytosis - a newly found activity of substance P residing in its N-terminal tetrapeptide sequence.  Biochem Biophys Res Commun. 1980;  94 1445-1451
  • 161 Hartung H P, Toyka K V. Activation of macrophages by substance P: induction of oxidative burst and thromboxane release.  Eur J Pharmacol. 1983;  89 301-305
  • 162 Payan D G, Goetzl E J. Modulation of lymphocyte function by sensory neuropeptides.  J Immunol. 1985;  135 783s-786s
  • 163 Hartung H P, Wolters K, Toyka K V. Substance P: binding properties and studies on cellular responses in guinea pig macrophages.  J Immunol. 1986;  136 3856-3863
  • 164 Stanisz A M, Befus D, Bienenstock J. Differential effects of vasoactive intestinal peptide, substance P, and somatostatin on immunoglobulin synthesis and proliferations by lymphocytes from Peyer's patches, mesenteric lymph nodes, and spleen.  J Immunol. 1986;  136 152-156
  • 165 Ferreira S H, Lorenzetti B B, Bristow A F, Poole S. Interleukin-1 beta as a potent hyperalgesic agent antagonized by a tripeptide analogue.  Nature. 1988;  334 698-700
  • 166 Cunha F Q, Poole S, Lorenzetti B B, Ferreira S H. The pivotal role of tumour necrosis factor alpha in the development of inflammatory hyperalgesia.  Br J Pharmacol. 1992;  107 660-664
  • 167 Wood D D, Ihrie E J, Dinarello C A, Cohen P L. Isolation of an interleukin-1-like factor from human joint effusions.  Arthritis Rheum. 1983;  26 975-983
  • 168 Nouri A M, Panayi G S, Goodman S M. Cytokines and the chronic inflammation of rheumatic disease. I. The presence of interleukin-1 in synovial fluids.  Clin Exp Immunol. 1984;  55 295-302
  • 169 Waalen K, Duff G W, Forre O, Dickens E, Kvarnes L, Nuki G. Interleukin 1 activity produced by human rheumatoid and normal dendritic cells.  Scand J Immunol. 1986;  23 365-371
  • 170 Eastgate J A, Symons J A, Wood N C, Grinlinton F M, di Giovine F S, Duff G W. Correlation of plasma interleukin 1 levels with disease activity in rheumatoid arthritis.  Lancet. 1988;  2 706-709
  • 171 Hopkins S J, Humphreys M, Jayson M I. Cytokines in synovial fluid. I. The presence of biologically active and immunoreactive IL-1.  Clin Exp Immunol. 1988;  72 422-427
  • 172 Feldmann M, Brennan F M, Chantry D, Haworth C, Turner M, Abney E, Buchan G, Barrett K, Barkley D, Chu A. Cytokine production in the rheumatoid joint: implications for treatment.  Ann Rheum Dis. 1990;  49 480-486
  • 173 Hopkins S J, Meager A. Cytokines in synovial fluid: II. The presence of tumour necrosis factor and interferon.  Clin Exp Immunol. 1988;  73 88-92
  • 174 Saxne T, Palladino M A, Jr. , Heinegard D, Talal N, Wollheim F A. Detection of tumor necrosis factor alpha but not tumor necrosis factor beta in rheumatoid arthritis synovial fluid and serum.  Arthritis Rheum. 1988;  31 1041-1045
  • 175 Chu C Q, Field M, Feldmann M, Maini R N. Localization of tumor necrosis factor alpha in synovial tissues and at the cartilage-pannus junction in patients with rheumatoid arthritis.  Arthritis Rheum. 1991;  34 1125-1132
  • 176 Thornton S C, Por S B, Penny R, Richter M, Shelley L, Breit S N. Identification of the major fibroblast growth factors released spontaneously in inflammatory arthritis as platelet derived growth factor and tumour necrosis factor-alpha.  Clin Exp Immunol. 1991;  86 79-86
  • 177 Borzi R M, Arfilli L, Focherini M C, Pulsatelli L, Meliconi R. Circulating tumor necrosis factor alpha in rheumatoid arthritis.  Boll Soc Ital Biol Sper. 1993;  69 39-43
  • 178 Herbert M K, Holzer P. Interleukin-1β enhances capsaicin-induced neurogenic vasodilatation in the rat skin.  Br J Pharmacol. 1994;  111 681-686
  • 179 Herbert M K, Holzer P. Nitric oxide mediates the amplification by interleukin-1β of neurogenic vasodilatation in the rat skin.  Eur J Pharmacol. 1994;  260 89-93
  • 180 Herbert M K, Hering S. Tumor necrosis factor a prevents interleukin-1β from augmenting capsaicin-induced vasodilatation in the rat skin.  Eur J Pharmacol. 1995 ;  286 273-279
  • 181 Follenfant R L, Nakamura C raig, Henderson B, Higgs G A. Inhibition by neuropeptides of interleukin-1 beta-induced, prostaglandin-independent hyperalgesia.  Br J Pharmacol. 1989;  98 41-43
  • 182 Schweizer A, Feige U, Fontana A, Muller K, Dinarello C A. Interleukin-1 enhances pain reflexes. Mediation through increased prostaglandin E2 levels.  Agents Actions. 1988;  25 246-251
  • 183 Chapman P B, Lester T J, Casper E S, Gabrilove J L, Wong G Y, Kempin S J, Gold P J, Welt S, Warren R S, Starnes H F. Clinical pharmacology of recombinant tumor necrosis factor in patients with advanced cancer.  J Clin Oncol. 1987;  5 1942-1951
  • 184 Tewari A, Buhles W CJ, Starnes H FJ. Preliminary report: effects of interleukin-1 on platelet counts.  Lancet. 1990;  336 712-714
  • 185 Smith J W, Urba W J, Curti B D, Elwood L J, Steis R G, Janik J E, Sharfman W H, Miller L L, Fenton R G, Conlon K C. The toxic and hematologic effects of interleukin-1 alpha administered in a phase I trial to patients with advanced malignancies.  J Clin Oncol. 1992;  10 1141-1152

Priv.-Doz. Dr. med. Michael K. Herbert

Klinik für Anaesthesiologie der Universität Würzburg


Josef-Schneider-Straße 2

97080 Würzburg

Email: mherbert@anaesthesie.uni-wuerzburg.de