Advertisement

Zeitschrift für Rheumatologie

, Volume 77, Supplement 1, pp 24–30 | Cite as

Forschungsverbund Neuroimmunologie und Schmerz (Neuroimpa) im Forschungsnetz Muskuloskelettale Erkrankungen

  • H.-G. Schaible
  • H.-D. Chang
  • S. Grässel
  • H. Haibel
  • A. Hess
  • T. Kamradt
  • A. Radbruch
  • G. Schett
  • C. Stein
  • R. H. Straub
MSK-Forschungsverbund Neuroimmunologie und Schmerz (Neuroimpa)

Zusammenfassung

Hintergrund

Der Forschungsverbund Neuroimmunologie und Schmerz (Neuroimpa) untersucht die Bedeutung der Beziehungen zwischen dem Immunsystem und dem Nervensystem bei muskuloskeletalen Erkrankungen für die Entstehung von Schmerzen und für den Verlauf von Frakturheilung und Arthritiden.

Methodik

Das Methodenspektrum umfasst Untersuchungen an Einzelzellen, In-vivo-Modelle von Arthritis und Frakturheilung, bildgebende Verfahren zum Studium von Gehirnfunktionen an Tier und Mensch sowie die Analyse von Patientendaten.

Ergebnisse

Proinflammatorische Zytokine tragen über neuronale Zytokinrezeptoren signifikant zur Entstehung von Gelenkschmerzen bei. Immunzellen sezernieren Opioidpeptide, die über Opioidrezeptoren peripherer Nozizeptoren hypoalgetisch wirken. Die Knochenneubildung nach Fraktur wird durch das Nervensystem signifikant unterstützt. Das sympathische Nervensystem fördert die Entwicklung immunologisch induzierter Arthritiden. Die Studien zeigen ein bedeutsames analgetisches Potenzial der Neutralisierung von proinflammatorischen Zytokinen und von selektiv peripher wirkenden Opioiden. Ferner zeigen sie, dass die Modulation neuronaler Mechanismen muskuloskeletale Krankheitsverläufe günstig beeinflussen kann.

Diskussion

Eingriffe in die Interaktionen zwischen dem Immunsystem und dem Nervensystem bergen ein großes therapeutisches Potenzial für die Behandlung von muskuloskeletalen Erkrankungen und Schmerzen.

Schlüsselwörter

Immunsystem Nervensystem Muskuloskelettale Erkrankungen Opioide Proinflammatorische Zytokine 

Research consortium Neuroimmunology and pain in the research network musculoskeletal diseases

Abstract

Background

The research consortium Neuroimmunology and Pain (Neuroimpa) explores the importance of the relationships between the immune system and the nervous system in musculoskeletal diseases for the generation of pain and for the course of fracture healing and arthritis.

Material and methods

The spectrum of methods includes analyses at the single cell level, in vivo models of arthritis and fracture healing, imaging studies on brain function in animals and humans and analysis of data from patients.

Results

Proinflammatory cytokines significantly contribute to the generation of joint pain through neuronal cytokine receptors. Immune cells release opioid peptides which activate opioid receptors at peripheral nociceptors and thereby evoke hypoalgesia. The formation of new bone after fractures is significantly supported by the nervous system. The sympathetic nervous system promotes the development of immune-mediated arthritis. The studies show a significant analgesic potential of the neutralization of proinflammatory cytokines and of opioids which selectively inhibit peripheral neurons. Furthermore, they show that the modulation of neuronal mechanisms can beneficially influence the course of musculoskeletal diseases.

Discussion

Interventions in the interactions between the immune system and the nervous system hold a great therapeutic potential for the treatment of musculoskeletal diseases and pain.

Keywords

Immune system Nervous system Musculoskeletal diseases Opioids Proinflammatory cytokines 

Notes

Einhaltung ethischer Richtlinien

Interessenkonflikt

H.-G. Schaible, H.-D. Chang, S. Grässel, H. Haibel, A. Hess, T. Kamradt, A. Radbruch, G. Schett, C. Stein und R.H. Straub geben an, dass kein Interessenkonflikt besteht.

Alle beschriebenen Untersuchungen am Menschen wurden mit Zustimmung der zuständigen Ethik-Kommission, im Einklang mit nationalem Recht sowie gemäß der Deklaration von Helsinki von 1975 (in der aktuellen, überarbeiteten Fassung) durchgeführt. Von allen beteiligten Patienten liegt eine Einverständniserklärung vor.

Literatur

  1. 1.
    Baddack-Werncke U et al (2017) Cytotoxic T cells modulate inflammation and endogenous opioid analgesia in chronic arthritis. J Neuroinflammation 14:30CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Celik MÖ et al (2016) Leukocyte opioid receptors mediate analgesia via Ca2+-regulated release of opioid peptides. Brain Behav Immun 57:227–242CrossRefPubMedGoogle Scholar
  3. 3.
    Del Vecchio G et al (2017) Novel opioid analgesics and side effects. ACS Chem Neurosci 8:1638–1640CrossRefPubMedGoogle Scholar
  4. 4.
    Ebbinghaus M et al (2012) The anti-inflammatory effects of sympathectomy in murine antigen-induced arthritis are associated with a reduction of Th1 and Th17 responses. Ann Rheum Dis 71:253–261CrossRefPubMedGoogle Scholar
  5. 5.
    Ebbinghaus M et al (2017) Interleukin-17A is involved in mechanical hyperalgesia but not in the severity of murine antigen-induced arthritis. Sci Rep 7:10334CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Ebbinghaus M et al (2015) Interleukin-6-dependent influence of nociceptive sensory neurons on antigen-induced arthritis. Arthritis Res Ther 17:334CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Ebbinghaus M et al (2012) The role of interleukin-1ß in arthritic pain: main involvement in thermal but not in mechanical hyperalgesia in rat antigen-induced arthritis. Arthritis Rheumatol 64:3897–3907CrossRefGoogle Scholar
  8. 8.
    Eitner A et al (2017) Mechanisms of osteoarthritic pain. Studies in humans and experimental models. Front Mol Neurosci 10:349CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Eitner A et al (2017) Pain sensation in human osteoarthritic knee joints is strongly enhanced by diabetes mellitus. Pain 158:1743–1753CrossRefPubMedGoogle Scholar
  10. 10.
    Eitner A et al (2013) The innervation of synovium of human osteoarthritic joints in comparison with normal rat and sheep synovium. Osteoarthr Cartil 21:1383–1391CrossRefPubMedGoogle Scholar
  11. 11.
    Gayetskyy S et al (2014) Characterization and quantification of angiogenesis in rheumatoid arthritis in a mouse model using μCT. BMC Musculoskelet Disord 15:298CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Gonzalez-Rodrıguez S et al (2017) Polyglycerol-opioid conjugate produces analgesia devoid of side effects. eLife 6:e27081.  https://doi.org/10.7554/eLife.27081 PubMedPubMedCentralGoogle Scholar
  13. 13.
    Grässel S (2014) The role of peripheral nerve fibers and their neurotransmitters in cartilage and bone physiology and pathophysiology. Arthritis Res Ther 6:485CrossRefGoogle Scholar
  14. 14.
    Grässel S, Muschter D (2018) Do neuroendocrine peptides and their receptors qualify as novel therapeutic targets in osteoarthritis? Int J Mol Sci 19:367CrossRefPubMedCentralGoogle Scholar
  15. 15.
    Heindl-Erdmann C et al (2010) Combining functional magnetic resonance imaging with mouse genomics: new options in pain research. Neuroreport 21:29–33CrossRefPubMedGoogle Scholar
  16. 16.
    Hess A et al (2011) Blockade of TNF-α rapidly inhibits pain responses in the central nervous system. PNAS 108:3731–3736CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Hess A et al (2018) Pain but not inflammation impairs cognition during arthritis in double transgenic mice. Submitted.Google Scholar
  18. 18.
    Hess A et al (2015) Functional brain imaging reveals rapid blockade of abdominal pain response upon anti-TNF therapy in Crohn’s disease. Gastroenterology 149:864CrossRefPubMedGoogle Scholar
  19. 19.
    Irmler IM et al (2014) Amelioration of experimental arthritis by stroke-induced immunosuppression is independent of Treg cell function. Ann Rheum Dis 73:2183–2191CrossRefPubMedGoogle Scholar
  20. 20.
    Jacobi CLJ, Stein C (2018) Inflammatory-linked changes in CpG island methylation of three opioid peptide genes in a rat model for pain. PLoS ONE.  https://doi.org/10.1371/journal.pone.0191698 PubMedPubMedCentralGoogle Scholar
  21. 21.
    Jagla C et al (2014) Peripheral opioid receptor blockade increases postoperative morphine demands—A randomized, double-blind, placebo-controlled trial. Pain 155:2056–2062CrossRefPubMedGoogle Scholar
  22. 22.
    Jochmann E et al (2015) Antigen-induced arthritis in rats is associated with increased growth-associated protein GAP-43-positive intraepidermal nerve fibres remote from the joint. Arthritis Res Ther 17:299CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Klatt S et al (2016) Peripheral elimination of the sympathetic nervous system stimulates immunocyte retention in lymph nodes and ameliorates collagen type II arthritis. Brain Behav Immun 54:201–210CrossRefPubMedGoogle Scholar
  24. 24.
    König C et al (2016) Involvement of spinal Interleukin-6 trans-signaling in the induction of hyperexcitability of deep dorsal horn neurons by spinal Tumor Necrosis Factor–α. J Neurosci 36:9782–9791CrossRefPubMedGoogle Scholar
  25. 25.
    König C et al (2014) Involvement of peripheral and spinal Tumor-Necrosis-Factor α (TNFα) in spinal cord hyperexcitability during knee joint inflammation in rat. Arthritis Rheumatol 66:599–609CrossRefPubMedGoogle Scholar
  26. 26.
    Kreitz S et al (2018) A new analysis of resting state connectivity and graph theory reveals distinctive short-term modulations due to whisker stimulation in rats. https://www.biorxiv.org/content/early/2017/11/21/223057  https://doi.org/10.1101/223057 Google Scholar
  27. 27.
    Leuchtweis J et al (2014) Enhanced neurogenesis in the hippocampal dentate gyrus during antigen-induced arthritis in adult rat—a crucial role of immunization. PLoS ONE 9:e89258CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Maddila CS et al (2017) B lymphocytes express Pomc mRNA, processing enzymes and β—Endorphin in painful inflammation. J Neuroimmune Pharmacol 12:180–186CrossRefPubMedGoogle Scholar
  29. 29.
    Massier J et al (2015) Effects of differently activated rodent macrophages on sensory neurons. Implications for arthritis pain. Arthritis Rheumatol 67:2263–2272CrossRefPubMedGoogle Scholar
  30. 30.
    Natura G et al (2013) Neuronal prostaglandin E2 receptor subtype EP3 mediates antinociception during inflammation. PNAS 110:13648–13653CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Niedermair T et al (2014) Absence of substance P and the sympathetic nervous system impact on bone structure and chondrocyte differentiation in an adult model of enchondral ossification. Matrix Biol 38:22–35CrossRefPubMedGoogle Scholar
  32. 32.
    Niedermair T et al (2018) Substance P modulates bone remodeling properties of murine osteoblasts and osteoclasts. Sci Rep : (in Revision)Google Scholar
  33. 33.
    Opolka et al (2012) Substance P and norepinephrine modulate murine chondrocyte proliferation and apoptosis. Arthritis Rheumatol 64:729–739CrossRefGoogle Scholar
  34. 34.
    Pannell M et al (2016) Adoptive transfer of M2 macrophages reduces neuropathic pain via opioid peptides. J Neuroinflammation 13:262CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Pongratz G, Straub RH (2013) Role of peripheral nerve fibres in acute and chronic inflammation in arthritis. Nat Rev Rheumatol 9:117–126CrossRefPubMedGoogle Scholar
  36. 36.
    Rech J et al (2013) Association of brain functional magnetic resonance activity with response to tumor necrosis factor inhibition. Arthritis Rheumatol 65:325–333CrossRefGoogle Scholar
  37. 37.
    Reinecke H et al (2015) Analgesic efficacy of opioids in chronic pain: recent meta-analyses. Br J Pharmacol 172:324–333CrossRefPubMedGoogle Scholar
  38. 38.
    Richter F et al (2012) Interleukin-17 sensitizes joint nociceptors for mechanical stimuli and contributes to arthritic pain through neuronal IL-17 receptors in rodents. Arthritis Rheumatol 64:4125–4134CrossRefGoogle Scholar
  39. 39.
    Schaible H‑G (2014) Nociceptive neurons detect cytokines in arthritis. Arthritis Res Ther 16:470CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Schaible H‑G, Straub RH (2014) Function of the sympathetic supply in acute and chronic experimental joint inflammation. Auton Neurosci 182:55–64CrossRefPubMedGoogle Scholar
  41. 41.
    Segond von Banchet G et al (2013) Neuronal IL-17 receptor upregulates TRPV4 but not TRPV1 receptors in DRG neurons and mediates mechanical but not thermal hyperalgesia. Mol Cell Neurosci 52:152–160CrossRefPubMedGoogle Scholar
  42. 42.
    Segond von Banchet G et al (2011) Molecular effects of Interleukin-1β on dorsal root ganglion neurons: prevention of ligand-induced internalization of the bradykinin 2 receptor and downregulation of G protein-coupled receptor kinase 2. Mol Cell Neurosci 46:262–271CrossRefGoogle Scholar
  43. 43.
    Segond von Banchet G et al (2016) Long-lasting activation of the transcription factor CREB in sensory neurons by interleukin-1ß during antigen-induced arthritis in rat—a mechanism of persistent arthritic pain? Arthritis Rheumatol 68:532–541CrossRefPubMedGoogle Scholar
  44. 44.
    Sergeeva M et al (2015) Response to peripheral immune stimulation within the brain: magnetic resonance imaging perspective of treatment success. Arthritis Res Ther 17:268CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Spahn V et al (2017) A nontoxic pain killer designed by modeling of pathological receptor conformations. Science 355:966–969CrossRefPubMedGoogle Scholar
  46. 46.
    Stangl H et al (2015) Catecholaminergic-to-cholinergic transition of sympathetic nerve fibers is stimulated under healthy but under inflammatory arthritic conditions. Brain Behav Immun 46:180–191CrossRefPubMedGoogle Scholar
  47. 47.
    Stein C (2016) Opioid receptors. Annu Rev Med 67:433–451CrossRefPubMedGoogle Scholar
  48. 48.
    Straub RH (2017) The brain and immune system prompt energy shortage in chronic inflammation and ageing. Nature Rev Rheumatol 13:743–751CrossRefGoogle Scholar
  49. 49.
    Straub RH et al (2011) Increased density of sympathetic nerve fibers in metabolically activted fat tissue surrounding human synovium and mouse lymph nodes in arthritis. Arthritis Rheumatol 63:3234–3242CrossRefGoogle Scholar
  50. 50.
    Vazquez E et al (2012) Spinal interleukin-6 is an amplifier of arthritic pain. Arthritis Rheumatol 64:2233–2242CrossRefGoogle Scholar

Copyright information

© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2018

Authors and Affiliations

  • H.-G. Schaible
    • 1
  • H.-D. Chang
    • 2
  • S. Grässel
    • 3
  • H. Haibel
    • 4
  • A. Hess
    • 5
  • T. Kamradt
    • 6
  • A. Radbruch
    • 2
  • G. Schett
    • 7
  • C. Stein
    • 8
  • R. H. Straub
    • 9
  1. 1.Institut für Physiologie 1/Neurophysiologie, Universitätsklinikum JenaFriedrich Schiller Universität JenaJenaDeutschland
  2. 2.Deutsches Rheuma-Forschungszentrum Berlinein Institut der Leibniz-GemeinschaftBerlinDeutschland
  3. 3.Klinik und Poliklinik für Orthopädie, Experimentelle OrthopädieUniversitätsklinikum RegensburgRegensburgDeutschland
  4. 4.Abteilung für RheumatologieCharité Universitätsmedizin Berlin, Campus Benjamin FranklinBerlinDeutschland
  5. 5.Institut für PharmakologieUniversitätsklinikum Erlangen-NürnbergErlangenDeutschland
  6. 6.Institut für Immunologie, Universitätsklinikum JenaFriedrich Schiller Universität JenaJenaDeutschland
  7. 7.Klinik für Innere MedizinUniversitätsklinikum Erlangen-NürnbergErlangenDeutschland
  8. 8.Klinik für AnästhesieCharité Universitätsmedizin Berlin, Campus Benjamin FranklinBerlinDeutschland
  9. 9.Klinik für Innere Medizin 1Universitätsklinikum RegensburgRegensburgDeutschland

Personalised recommendations