Skip to main content
SpringerLink
Log in

Forschungsverbund Neuroimmunologie und Schmerz (Neuroimpa) im Forschungsnetz Muskuloskelettale Erkrankungen

Research consortium Neuroimmunology and pain in the research network musculoskeletal diseases

  • MSK-Forschungsverbund Neuroimmunologie und Schmerz (Neuroimpa)
  • Published:
Zeitschrift für Rheumatologie Aims and scope Submit manuscript

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.

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Literatur

  1. Baddack-Werncke U et al (2017) Cytotoxic T cells modulate inflammation and endogenous opioid analgesia in chronic arthritis. J Neuroinflammation 14:30

    Article  PubMed  PubMed Central  Google Scholar 

  2. Celik MÖ et al (2016) Leukocyte opioid receptors mediate analgesia via Ca2+-regulated release of opioid peptides. Brain Behav Immun 57:227–242

    Article  CAS  PubMed  Google Scholar 

  3. Del Vecchio G et al (2017) Novel opioid analgesics and side effects. ACS Chem Neurosci 8:1638–1640

    Article  PubMed  Google Scholar 

  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 71:253–261

    Article  CAS  PubMed  Google Scholar 

  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 7:10334

    Article  PubMed  PubMed Central  Google Scholar 

  6. Ebbinghaus M et al (2015) Interleukin-6-dependent influence of nociceptive sensory neurons on antigen-induced arthritis. Arthritis Res Ther 17:334

    Article  PubMed  PubMed Central  Google Scholar 

  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 64:3897–3907

    Article  CAS  Google Scholar 

  8. Eitner A et al (2017) Mechanisms of osteoarthritic pain. Studies in humans and experimental models. Front Mol Neurosci 10:349

    Article  PubMed  PubMed Central  Google Scholar 

  9. Eitner A et al (2017) Pain sensation in human osteoarthritic knee joints is strongly enhanced by diabetes mellitus. Pain 158:1743–1753

    Article  PubMed  Google Scholar 

  10. Eitner A et al (2013) The innervation of synovium of human osteoarthritic joints in comparison with normal rat and sheep synovium. Osteoarthr Cartil 21:1383–1391

    Article  CAS  PubMed  Google Scholar 

  11. Gayetskyy S et al (2014) Characterization and quantification of angiogenesis in rheumatoid arthritis in a mouse model using μCT. BMC Musculoskelet Disord 15:298

    Article  PubMed  PubMed Central  Google Scholar 

  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

    PubMed  PubMed Central  Google Scholar 

  13. Grässel S (2014) The role of peripheral nerve fibers and their neurotransmitters in cartilage and bone physiology and pathophysiology. Arthritis Res Ther 6:485

    Article  Google Scholar 

  14. Grässel S, Muschter D (2018) Do neuroendocrine peptides and their receptors qualify as novel therapeutic targets in osteoarthritis? Int J Mol Sci 19:367

    Article  PubMed Central  Google Scholar 

  15. Heindl-Erdmann C et al (2010) Combining functional magnetic resonance imaging with mouse genomics: new options in pain research. Neuroreport 21:29–33

    Article  PubMed  Google Scholar 

  16. Hess A et al (2011) Blockade of TNF-α rapidly inhibits pain responses in the central nervous system. PNAS 108:3731–3736

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hess A et al (2018) Pain but not inflammation impairs cognition during arthritis in double transgenic mice. Submitted.

  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 149:864

    Article  PubMed  Google Scholar 

  19. Irmler IM et al (2014) Amelioration of experimental arthritis by stroke-induced immunosuppression is independent of Treg cell function. Ann Rheum Dis 73:2183–2191

    Article  CAS  PubMed  Google Scholar 

  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

    PubMed  PubMed Central  Google Scholar 

  21. Jagla C et al (2014) Peripheral opioid receptor blockade increases postoperative morphine demands—A randomized, double-blind, placebo-controlled trial. Pain 155:2056–2062

    Article  CAS  PubMed  Google Scholar 

  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 17:299

    Article  PubMed  PubMed Central  Google Scholar 

  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 54:201–210

    Article  CAS  PubMed  Google Scholar 

  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 36:9782–9791

    Article  PubMed  Google Scholar 

  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 66:599–609

    Article  PubMed  Google Scholar 

  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. 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:e89258

    Article  PubMed  PubMed Central  Google Scholar 

  28. Maddila CS et al (2017) B lymphocytes express Pomc mRNA, processing enzymes and β—Endorphin in painful inflammation. J Neuroimmune Pharmacol 12:180–186

    Article  PubMed  Google Scholar 

  29. Massier J et al (2015) Effects of differently activated rodent macrophages on sensory neurons. Implications for arthritis pain. Arthritis Rheumatol 67:2263–2272

    Article  CAS  PubMed  Google Scholar 

  30. Natura G et al (2013) Neuronal prostaglandin E2 receptor subtype EP3 mediates antinociception during inflammation. PNAS 110:13648–13653

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 38:22–35

    Article  CAS  PubMed  Google Scholar 

  32. Niedermair T et al (2018) Substance P modulates bone remodeling properties of murine osteoblasts and osteoclasts. Sci Rep : (in Revision)

  33. Opolka et al (2012) Substance P and norepinephrine modulate murine chondrocyte proliferation and apoptosis. Arthritis Rheumatol 64:729–739

    Article  CAS  Google Scholar 

  34. Pannell M et al (2016) Adoptive transfer of M2 macrophages reduces neuropathic pain via opioid peptides. J Neuroinflammation 13:262

    Article  PubMed  PubMed Central  Google Scholar 

  35. Pongratz G, Straub RH (2013) Role of peripheral nerve fibres in acute and chronic inflammation in arthritis. Nat Rev Rheumatol 9:117–126

    Article  CAS  PubMed  Google Scholar 

  36. Rech J et al (2013) Association of brain functional magnetic resonance activity with response to tumor necrosis factor inhibition. Arthritis Rheumatol 65:325–333

    Article  CAS  Google Scholar 

  37. Reinecke H et al (2015) Analgesic efficacy of opioids in chronic pain: recent meta-analyses. Br J Pharmacol 172:324–333

    Article  CAS  PubMed  Google Scholar 

  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 64:4125–4134

    Article  CAS  Google Scholar 

  39. Schaible H‑G (2014) Nociceptive neurons detect cytokines in arthritis. Arthritis Res Ther 16:470

    Article  PubMed  PubMed Central  Google Scholar 

  40. Schaible H‑G, Straub RH (2014) Function of the sympathetic supply in acute and chronic experimental joint inflammation. Auton Neurosci 182:55–64

    Article  PubMed  Google Scholar 

  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 52:152–160

    Article  CAS  PubMed  Google Scholar 

  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 46:262–271

    Article  Google Scholar 

  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 68:532–541

    Article  CAS  PubMed  Google Scholar 

  44. Sergeeva M et al (2015) Response to peripheral immune stimulation within the brain: magnetic resonance imaging perspective of treatment success. Arthritis Res Ther 17:268

    Article  PubMed  PubMed Central  Google Scholar 

  45. Spahn V et al (2017) A nontoxic pain killer designed by modeling of pathological receptor conformations. Science 355:966–969

    Article  CAS  PubMed  Google Scholar 

  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 46:180–191

    Article  CAS  PubMed  Google Scholar 

  47. Stein C (2016) Opioid receptors. Annu Rev Med 67:433–451

    Article  CAS  PubMed  Google Scholar 

  48. Straub RH (2017) The brain and immune system prompt energy shortage in chronic inflammation and ageing. Nature Rev Rheumatol 13:743–751

    Article  CAS  Google Scholar 

  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 63:3234–3242

    Article  CAS  Google Scholar 

  50. Vazquez E et al (2012) Spinal interleukin-6 is an amplifier of arthritic pain. Arthritis Rheumatol 64:2233–2242

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institut für Physiologie 1/Neurophysiologie, Universitätsklinikum Jena, Friedrich Schiller Universität Jena, Teichgraben 8, 07743, Jena, Deutschland

    H.-G. Schaible

  2. Deutsches Rheuma-Forschungszentrum Berlin, ein Institut der Leibniz-Gemeinschaft, Berlin, Deutschland

    H.-D. Chang & A. Radbruch

  3. Klinik und Poliklinik für Orthopädie, Experimentelle Orthopädie, Universitätsklinikum Regensburg, Regensburg, Deutschland

    S. Grässel

  4. Abteilung für Rheumatologie, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Deutschland

    H. Haibel

  5. Institut für Pharmakologie, Universitätsklinikum Erlangen-Nürnberg, Erlangen, Deutschland

    A. Hess

  6. Institut für Immunologie, Universitätsklinikum Jena, Friedrich Schiller Universität Jena, Jena, Deutschland

    T. Kamradt

  7. Klinik für Innere Medizin, Universitätsklinikum Erlangen-Nürnberg, Erlangen, Deutschland

    G. Schett

  8. Klinik für Anästhesie, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Deutschland

    C. Stein

  9. Klinik für Innere Medizin 1, Universitätsklinikum Regensburg, Regensburg, Deutschland

    R. H. Straub

Authors
  1. H.-G. Schaible
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H.-D. Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S. Grässel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H. Haibel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A. Hess
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T. Kamradt
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A. Radbruch
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. G. Schett
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. C. Stein
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. R. H. Straub
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H.-G. Schaible.

Ethics declarations

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.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Schaible, HG., Chang, HD., Grässel, S. et al. Forschungsverbund Neuroimmunologie und Schmerz (Neuroimpa) im Forschungsnetz Muskuloskelettale Erkrankungen. Z Rheumatol 77 (Suppl 1), 24–30 (2018). https://doi.org/10.1007/s00393-018-0459-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00393-018-0459-9

Schlüsselwörter

Keywords

Search

Navigation