Cytotoxic T cells modulate inflammation and endogenous opioid analgesia in chronic arthritis.
This study examined the development of chronic pain, a cardinal symptom of rheumatoid arthritis (RA), in mice with antigen- and collagen-induced arthritis (ACIA). Since the role of CD8+T cells in arthritis is controversial, we investigated the consequences of CD8-depletion on arthritis development and opioid modulation of pain in this novel model of chronic autoimmune arthritis.



Disease severity in control and CD8-depleted animals was determined by histological assessment of knee-joint sections and measurement of autoantibody formation. Pain was evaluated by measuring mechanical allodynia and thermal hyperalgesia in von Frey and Hargreaves tests, respectively. The production and release of endogenous opioids and inflammatory cytokines was assessed in immunoassays.



In ACIA, mice display persistent mechanical allodynia and thermal hyperalgesia for more than 2 months after induction of arthritis. The blockade of peripheral opioid receptors with naloxone-methiodide (NLXM) transiently increased thermal hyperalgesia, indicating that endogenous opioid peptides were released in the arthritic joint to inhibit pain. CD8+T cell depletion did not affect autoantibody formation or severity of joint inflammation, but serum levels of the pro-inflammatory cytokines TNFα and IL-17 were increased. The release of opioid peptides from explanted arthritic knee cells and the NLXM effect were significantly reduced in the absence of CD8+T cells.



We have successfully modeled the development of chronic pain, a hallmark of RA, in ACIA. Furthermore, we detected a yet unknown protective role of CD8+T cells in chronic ACIA since pro-inflammatory cytokines rose and opioid peptide release decreased in the absence of these cells.
Department of Tumor Genetics and Immunogenetics, Max-Delbrück-Center of Molecular Medicine (MDC), Robert-Rössle-Strasse 10, 13125, Berlin, Germany.|Current address: DLR project management agency, Department for Health Research, Heinrich-Konen-Str. 1, 53227, Bonn, Germany.
Uta
U
Baddack-Werncke
Department of Anesthesiology and Critical Care Medicine, Charité Campus Benjamin Franklin, Hindenburgdamm 30, 12203, Berlin, Germany.
Melanie
M
Busch-Dienstfertig
Department of Anesthesiology and Critical Care Medicine, Charité Campus Benjamin Franklin, Hindenburgdamm 30, 12203, Berlin, Germany. saragonzalezrodriguez@gmail.com.|Current address: Instituto de Biología Molecular y Celular (IBMC), Av. de la Universidad s/n. Edif. Torregaitán, Elche, 03202, Alicante, Spain. saragonzalezrodriguez@gmail.com.
Sara
S
González-Rodríguez
Department of Anesthesiology and Critical Care Medicine, Charité Campus Benjamin Franklin, Hindenburgdamm 30, 12203, Berlin, Germany.|Current address: Santhosh Nursing Home, Darsi, Prakasam District, Andhra Pradesh, 523247, India.
Santhosh Chandar
SC
Maddila
Department of Tumor Genetics and Immunogenetics, Max-Delbrück-Center of Molecular Medicine (MDC), Robert-Rössle-Strasse 10, 13125, Berlin, Germany.
Jenny
J
Grobe
Department of Tumor Genetics and Immunogenetics, Max-Delbrück-Center of Molecular Medicine (MDC), Robert-Rössle-Strasse 10, 13125, Berlin, Germany.
Martin
M
Lipp
Department of Anesthesiology and Critical Care Medicine, Charité Campus Benjamin Franklin, Hindenburgdamm 30, 12203, Berlin, Germany.
Christoph
C
Stein
Department of Tumor Genetics and Immunogenetics, Max-Delbrück-Center of Molecular Medicine (MDC), Robert-Rössle-Strasse 10, 13125, Berlin, Germany.
Gerd
G
Müller
D000701:Analgesics, Opioid / Q000378:metabolism*; D000818:Animals; D000906:Antibodies / Q000009:adverse effects; D001169:Arthritis, Experimental / Q000150:complications* / Q000276:immunology / Q000473:pathology*; D016827:CD8 Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D003094:Collagen / Q000633:toxicity; D004195:Disease Models, Animal; D004745:Enkephalins / Q000378:metabolism; D005260:Female; D005620:Freund's Adjuvant / Q000276:immunology / Q000633:toxicity; D007839:Functional Laterality; D006930:Hyperalgesia / Q000209:etiology; D007249:Inflammation / Q000209:etiology* / Q000473:pathology; D008715:Methionine / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010147:Pain Measurement; D017288:Pain Threshold / Q000502:physiology; D013997:Time Factors
D000701:Analgesics, Opioid; D000906:Antibodies; D016827:CD8 Antigens; D004745:Enkephalins; D003094:Collagen; D005620:Freund's Adjuvant; D008715:Methionine
Analgesia; CD8 cells; Opioid peptides; Rheumatoid arthritis