Die Lokalisation des Neurokinin 1-Rezeptors im Hüftgelenk von Patienten mit schmerzhafter Osteoarthrose

Zusammenfassung

Einleitung: Verschiedene Studien konnten zeigen, dass Substanz P (SP) enthaltende afferente Nervenfasern eine Rolle bei der Entzündungsinduktion und der Schmerzwahrnehmung in Arthrosegelenken spielen. Die Effekte des Neuropeptids SP werden hauptsächlich über den Tachykinin Rezeptor Neurokinin 1 (NK1-R) vermittelt. Studienziel: Das Ziel der vorliegenden Studie war es, den NK1-R erstmalig in menschlichem Gelenkgewebe darzustellen. Methodik: Drei Patienten mit schmerzhafter Osteoarthrose der Hüfte (Gruppe 1) und drei Fälle mit medialer Oberschenkelhalsfraktur ohne Gelenkdegeneration (Gruppe 2, Kontrollgruppe) wurden zur Implantation einer Hüftendoprothese die Gelenkkapsel reseziert. In Gruppe 1 entfernten wir zusätzlich das Bindegewebe der Fossa acetabuli. Die Gewebe wurden daraufhin immersionsfixiert, am Kryotom in 50 µm Schichten geschnitten und der NK1-R immunhistochemisch nachgewiesen. Ergebnisse: Der NK1-Rezeptor konnte in beiden Gruppen identifiziert werden. Er war auf der Wand von venösen Gefäßen, auf Schwann Zellen von Nervenbündeln und auf Nervenfasern lokalisiert. Das Verteilungsmuster des Rezeptors auf den verschiedenen Gewebsstrukturen war in beiden Gruppen vergleichbar, allerdings schien die Anzahl der Zellen mit NK1-Immunreaktivität in der Osteoarthrosegruppe höher zu sein als in der Vergleichsgruppe. Schlussfolgerung: Mit der vorliegenden Studie konnte erstmalig der NK1-R in menschlichem Gelenkgewebe nachgewiesen werden. Die Dichte der NK1-R-positiven Strukturen schien in der Osteoarthrosegruppe höher zu sein als in der Kontrollgruppe. Die Lokalisation des Rezeptors auf verschiedenen Zelltypen legt multiple Effekte von SP in normalen und osteoarthrotischen Gelenken nahe.

Abstract

Introduction: Recent studies on osteoarthritis have focused on nociceptive substance P (SP) containing afferent nerve fibres. The effects of SP are known to be mainly mediated by the tachykinin receptor neurokinin 1 (NK1-R). Aim: The aim of the present study was to demonstrate the NK1-R in human joint tissues. Methods: The hip joint capsule of three patients with painful hip osteoarthritis (Group 1), three patients with femoral neck fracture showing no cartilage destruction (Group 2, controls) and the soft tissue of the fossa acetabuli of Group 1 were resected during hip arthroplasty implantation. The tissue samples were cut into small blocks and immersion-fixed in Zamboni's fixative. The specimens were frozen, cut into 50 µm sections and immunostained using a standard immunohistochemical staining protocol. Results: In Groups 1 and 2 the NK1-receptor was localised in the wall of venous vessels, on Schwann cells of nerve bundles and on nerve fibres. In the osteoarthritis group the staining pattern was similar but the number of NK1-bearing cell structures seemed to be enhanced. Conclusions: The present study provides the first evidence of NK1-R in the human hip joint. In patients with painful osteoarthritis the density of NK1-R-positive cell structures seemed to be increased. The localisation of the NK1 receptor on different cell types suggests multiple effects of SP in normal and osteoarthritic joints.

Schlüsselwörter

Osteoarthrose - Neurokinin 1-Rezeptor - Substanz P - neurogene Entzündung - Schmerz

Key words

Osteoarthritis - neurokinin 1 receptor - substance P - neurogenic inflammation - pain

Literatur

• 1 Remberger K. Gelenke, Bursen, Sehnenscheiden und Menisci. In: Eder M, Gedigk P (eds). Allgemeine Pathologie und Pathologische Anatomie. Springer, Berlin Heidelberg 1990; 848-866
• 2 Kidd B L, Urban L A. Mechanisms of inflammatory pain.  Br J Anaesth. 2001;  87 3-11
• 3 Jancso N, Jancso-Gabor A, Szolcsanyi J. Direct evidence for neurogenic inflammation and its prevention by denervation and by pretreatment with capsaicin.  Br J Pharmacol. 1967;  31 138-151
• 4 Olgart L, Gazelius B, Brodin E, Nilsson G. Release of substance P-like immunoreactivity from the dental pulp.  Acta Physiol Scand. 1977;  101 510-512
• 5 Yaksh T L. Substance P release from knee joint afferent terminals: modulation by opioids.  Brain Res. 1988;  458 319-324
• 6 Brain S D, Williams T J. Substance P regulates the vasodilator activity of calcitonin gene-related peptide.  Nature. 1988;  335 73-75
• 7 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. 1986;  379 407-416
• 8 Lembeck F, Holzer P. Substance P as neurogenic mediator of antidromic vasodilation and neurogenic plasma extravasation.  Naunyn Schmiedebergs Arch Pharmacol. 1979;  310 175-183
• 9 Garrett N E, Kidd B L, Cruwys S C, Tomlinson D R. Changes in preprotachykinin mRNA expression and substance P levels in dorsal root ganglia of monoarthritic rats: comparison with changes in synovial substance P levels.  Brain Res.. 1995;  675 203-207
• 10 Lam F Y, Ferrell W R. Capsaicin suppresses substance P-induced joint inflammation in the rat.  Neurosci Lett. 1989;  105 55-108
• 11 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
• 12 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
• 13 Devillier P, Weill B, Renoux M, Menkes C, Pradelles P. Elevated levels of tachykinin-like immunoreactivity in joint fluids from patients with rheumatic inflammatory diseases.  N Engl J Med. 1986;  314 1323
• 14 Lotz M, Carson D A, Vaughan J H. Substance P activation of rheumatoid synoviocytes: neural pathway in pathogenesis of arthritis.  Science. 1987;  235 893-895
• 15 Lotz M, Vaughan J H, Carson D A. Effect of neuropeptides on production of inflammatory cytokines by human monocytes.  Science. 1988;  241 1218-1221
• 16 Lam F Y, Ferrell W R. Specific neurokinin receptors mediate plasma extravasation in the rat knee joint.  Br J Pharmacol. 1991;  103 1263-1267
• 17 Regoli D, Boudon A, Fauchere J L. Receptors and antagonists for substance P and related peptides.  Pharmacol Rev. 1994;  46 551-599
• 18 Maggi C A. The troubled story of tachykinins and neurokinins.  Trends Pharmacol Sci. 2000;  21 173-175
• 19 Castro A R, Pinto M, Lima D, Tavares I. Nociceptive spinal neurons expressing NK1 and GABAB receptors are located in lamina I.  Brain Res. 2004;  1003 77-85
• 20 Mazzone S B, Hinrichsen C F, Geraghty D P. Substance P receptors in brain stem respiratory centers of the rat: regulation of NK1 receptors by hypoxia.  J Pharmacol Exp Ther. 1997;  282 1547-1556
• 21 Aicher S A, Punnoose A, Goldberg A. mu-Opioid receptors often colocalize with the substance P receptor (NK1) in the trigeminal dorsal horn.  J Neurosci. 2000;  20 4345-4354
• 22 Carlton S M, Zhou S, Coggeshall R E. Localization and activation of substance P receptors in unmyelinated axons of rat glabrous skin.  Brain Res. 1996;  734 103-108
• 23 Grkovic I, Anderson C R. Distribution of immunoreactivity for the NK1 receptor on different subpopulations of sympathetic preganglionic neurons in the rat.  J Comp Neurol. 1996;  374 376-386
• 24 Hanesch U. Neuropeptides in dural fine sensory nerve endings - involvement in neurogenic inflammation?.  Prog Brain Res. 1996;  113 299-317
• 25 Ljung B O, Alfredson H, Forsgren S. Neurokinin 1-receptors and sensory neuropeptides in tendon insertions at the medial and lateral epicondyles of the humerus. Studies on tennis elbow and medial epicondylalgia.  J Orthop Res. 2004;  22 321-327
• 26 Mantyh C R, Vigna S R, Maggio J E, Mantyh P W, Bollinger R R, Pappas T N. Substance P binding sites on intestinal lymphoid aggregates and blood vessels in inflammatory bowel disease correspond to authentic NK-1 receptors.  Neurosci Lett. 1994;  178 255-259
• 27 Stewart-Lee A, Burnstock G. Actions of tachykinins on the rabbit mesenteric artery: substance P and [Glp6,L-Pro9]SP6-11 are potent agonists for endothelial neurokinin-1 receptors.  Br J Pharmacol. 1989;  97 1218-1224
• 28 Shimizu T, Koto A, Suzuki N, Morita Y, Takao M, Otomo S, Fukuuchi Y. Occurrence and distribution of substance P receptors in the cerebral blood vessels of the rat.  Brain Res. 1999;  830 372-378
• 29 Yip L, Kwok Y N, Buchan A M. Cellular localization and distribution of neurokinin-1 receptors in the rat stomach.  Auton Neurosci. 2003;  104 95-108
• 30 Collins J J, Usip S, McCarson K E, Papka R E. Sensory nerves and neuropeptides in uterine cervical ripening.  Peptides. 2002;  23 167-183
• 31 Ho W Z, Lai J P, Zhu X H, Uvaydova M, Douglas S D. Human monocytes and macrophages express substance P and neurokinin-1 receptor.  J Immunol. 1997;  159 5654-5660
• 32 Lai J P, Douglas S D, Zhao M, Ho W Z. Quantification of substance P mRNA in human mononuclear phagocytes and lymphocytes using a mimic-based RT-PCR.  J Immunol Methods. 1999;  230 149-157
• 33 Goto T, Yamaza T, Kido M A, Tanaka T. Light- and electron-microscopic study of the distribution of axons containing substance P and the localization of neurokinin-1 receptor in bone.  Cell Tissue Res. 1998;  293 87-93
• 34 Goto T, Tanaka T. Tachykinins and tachykinin receptors in bone.  Microsc Res Tech. 2002;  58 91-97
• 35 Abbadie C, Brown J L, Mantyh P W, Basbaum A I. Spinal cord substance P receptor immunoreactivity increases in both inflammatory and nerve injury models of persistent pain.  Neuroscience. 1996;  70 201-209
• 36 Honoré P, Menning M P, Rogers S D, Nichols M L, Basbaum A I, Besson J M, Mantyh P W. Spinal substance P receptor expression and internalization in acute, short-term, and long-term inflammatory pain states.  J Neurosci. 1999;  19 7670-7678
• 37 McCarson K E, Krause J E. NK-1 and NK-3 type tachykinin receptor mRNA expression in the rat spinal cord dorsal horn is increased during adjuvant or formalin-induced nociception.  J Neurosci. 1994;  14 712-720
• 38 Krause J E, DiMaggio D A, McCarson K E. Alterations in neurokinin 1 receptor gene expression in models of pain and inflammation.  Can J Physiol Pharmacol. 1995;  73 854-859
• 39 Schäfer M K, Nohr D, Krause J E, Weihe E. Inflammation-induced upregulation of NK1 receptor mRNA in dorsal horn neurones.  Neuroreport. 1993;  4 1007-1010
• 40 McCarson K E. Central and peripheral expression of neurokinin-1 and neurokinin-3 receptor and substance P-encoding messenger RNAs: peripheral regulation during formalin-induced inflammation and lack of neurokinin receptor expression in primary afferent sensory neurons.  Neuroscience. 1999;  93 361-370
• 41 Saxler G, Löer F, Skumavc M, Hanesch U. Localization of SP- and CGRP-immunopositive nerve fibres in the hip joint of patients with painful osteoarthritis and of patients with painless failed hip arthroplasties. (Artikel eingereicht)
• 42 Kido M A, Yamaza T, Goto T, Tanaka T. Immunocytochemical localization of substance P neurokinin-1 receptors in rat gingival tissue.  Cell Tissue Res. 1999;  297 213-222
• 43 Marshall K W, Theriault E, Homonko D A. Distribution of substance P and calcitonin gene related peptide immunoreactivity in the normal feline knee.  J Rheumatol. 1994;  21 883-889
• 44 Witonski D, Wagrowska-Danielewicz M. Distribution of substance-P nerve fibers in the knee joint in patients with anterior knee pain syndrome. A preliminary report.  Knee Surg Sports Traumatol Arthrosc. 1999;  7 177-183
• 45 Wojtys E M, Beaman D N, Glover R A, Janda D. Innervation of the human knee joint by substance-P fibers.  Arthroscopy. 1990;  6 254-263
• 46 Lembeck F. Mediators of vasodilatation in the skin.  Br J Dermatol. 1983;  109 1-9
• 47 Lam F Y, Ferrell W R. Mediators of substance P-induced inflammation in the rat knee joint.  Agents Actions. 1990;  31 298-307
• 48 McDougall J J, Karimian S M, Ferrell W R. Alteration of substance P-mediated vasodilatation and sympathetic vasoconstriction in the rat knee joint by adjuvant-induced inflammation.  Neurosci Lett. 1994;  174 127-129
• 49 Heppelmann B, Pawlak M. Sensitisation of articular afferents in normal and inflamed knee joints by substance P in the rat.  Neurosci Lett. 1997;  223 97-100
• 50 Pawlak M, Schmidt R F, Heppelmann B, Hanesch U. The neurokinin-1 receptor antagonist RP 67580 reduces the sensitization of primary afferents by substance P in the rat.  Eur J Pain. 2001;  5 69-79
• 51 De Felipe C, Herrero J F, O'Brien J A, Palmer J A, Doyle C A, Smith A J, Laird J M, Belmonte C, Cervero F, Hunt S P. Altered nociception, analgesia and aggression in mice lacking the receptor for substance P.  Nature. 1998;  392 394-397
• 52 Hong S K, Hans J S, Min S S, Hwang J M, Kim Y I, Na H S, Yoon Y W, Han H C. Local neurokinin-1 receptor in the knee joint contributes to the induction, but not maintenance, of arthritic pain in the rat.  Neurosci Lett. 2002;  322 21-24
• 53 Keeble J E, Brain S D. A role for substance P in arthritis?.  Neuroscience Let. 2004;  361 176-179
• 54 McDougall J J, Hanesch U, Pawlak M, Schmidt R F. Participation of NK1 receptors in nociceptin-induced modulation of rat knee joint mechanosensitivity.  Exp Brain Res. 2001;  137 249-253
• 55 Sakai K, Matsuno H, Tsuji H, Tohyama M. Substance P receptor (NK1) gene expression in synovial tissue in rheumatoid arthritis and osteoarthritis.  Scand J Rheumatol. 1998;  27 135-141
• 56 Seegers H C, Avery P S, McWilliams D F, Haywood L, Walsh D A. Combined effect of bradykinin B2 and neurokinin-1 receptor activation on endothelial cell proliferation in acute synovitis.  FASEB J. 2004;  18 762-764
• 57 Sluka K A, Milton M A, Willis W D, Westlund K N. Differential roles of neurokinin 1 and neurokinin 2 receptors in the development and maintenance of heat hyperalgesia induced by acute inflammation.  Br J Pharmacol. 1997;  120 1263-1273