Collagen antibody–induced arthritis evokes persistent pain with spinal glial involvement and transient prostaglandin dependency

Abstract

Objective. Pain is one of the most debilitating symptoms reported by rheumatoid arthritis (RA) patients. While the collagen antibody-induced arthritis (CAIA) model is used for studying the effector phase of RA pathologic progression, it has not been evaluated as a model for studies of pain. Thus, this study was undertaken to examine pain-like behavior induced by anticollagen antibodies and to assess the effect of currently prescribed analgesics for RA. In addition, the involvement of spinal glia in antibody-induced pain was explored.Methods. CAIA was induced in mice by intravenous injection of a collagen antibody cocktail, followed by intraperitoneal injection of lipopolysaccharide. Disease severity was assessed by visual and histologic examination. Pain-like behavior and the antinociceptive effect of diclofenac, buprenorphine, gabapentin, pentoxifylline, and JNK-interacting protein 1 were examined in mechanical stimulation experiments. Spinal astrocyte and microglia reactivity were investigated by real-time polymerase chain reaction and immunohistochemistry.Results. Following the induction of CAIA, mice developed transient joint inflammation. In contrast, pain-like behavior was observed prior to, and outlasted, the visual signs of arthritis. Whereas gabapentin and buprenorphine attenuated mechanical hypersensitivity during both the inflammatory and postinflammatory phases of arthritis, diclofenac was antinociceptive only during the inflammatory phase. Spinal astrocytes and microglia displayed time-dependent signs of activation, and inhibition of glial activity reversed CAIA-induced mechanical hypersensitivity.Conclusion. CAIA represents a multifaceted model for studies exploring the mechanisms of pain induced by inflammation in the articular joint. Our findings of a time-dependent prostaglandin and spinal glial contribution to antibody-induced pain highlight the importance of using appropriate disease models to assess joint-related pain.

Remaining Pain in Early Rheumatoid Arthritis Patients Treated With Methotrexate

“…However, if dysregulated pain thresholds, hyperalgesia, and allodynia have been established, these conditions are usually not reversible by immune suppression. Notably, similar patterns have been shown in models of transient experimental arthritis, where the initial joint inflammation caused a long‐lasting pain‐like behavior, persisting after the inflammation had resolved and also unresponsive to antiinflammatory drugs 29. Likewise, remaining pain based on peripheral sensitization in RA patients is a challenge for therapy, where further immune suppression is unlikely to have pain‐relieving effects.…”

Orthopedic surgery modulates neuropeptides and BDNF expression at the spinal and hippocampal levels

“…For nocifensive behavior in a femoral pin placement and fracture model, Majuta et al (50) gently and repeatedly pressed, with thumb and forefinger, the thigh of the fractured hind limb for 2 min. This is different from our protocol of carrying out the von Frey filament test no later than 2 wk after fracture, when the leg is not completely stable (50,52,53).…”

In vivo therapeutic efficacy of TNFα silencing by folate-PEG-chitosan-DEAE/siRNA nanoparticles in arthritic mice

“…Severity scores of (B) synovitis, (C) bone erosion and (D) cartilage destruction were assessed on day 10 by two investigators blinded to origin of the samples and using the already-described scoring method. 39 (E) Serum levels of CTX-II degradation products measured by ELISA. Values are the means ± SEM of eight mice (groups 1-4) and five mice (group 5).…”

“…Three sections were examined by digital EVOS light microscopy (Electron Microscopy Sciences, Hatfield, PA, USA) at 20× magnification to evaluate synovitis, bone erosion and cartilage damage. A scoring system, consisting of three grades per condition, as described by Bas et al, 39 was employed by two investigators blinded to origin of the samples. Synovial inflammation scores were assigned as: 0= no inflammation, 1= slight thickening of the synovial layer and/or some inflammatory cells in the sub-lining, 2= moderate infiltration of the sub-lining and 3= markedto-severe infiltration.…”

“…Cartilage destruction scores were as follows: 0= normal cartilage, 1= cartilage surface irregularities, 2= minor-tomoderate loss of surface cartilage and 3= marked cartilage destruction with loss of surface cartilage. 39 Tissue sections stained with toluidine blue were evaluated for proteoglycan to estimate cartilage structure condition. 40 …”