Animal models of rheumatoid pain: experimental systems and insights

Abstract

Severe chronic pain is one of the hallmarks and most debilitating manifestations of inflammatory arthritis. It represents a significant problem in the clinical management of patients with common chronic inflammatory joint conditions such as rheumatoid arthritis, psoriatic arthritis and spondyloarthropathies. The functional links between peripheral inflammatory signals and the establishment of the neuroadaptive mechanisms acting in nociceptors and in the central nervous system in the establishment of chronic and neuropathic pain are still poorly understood, representing an area of intense study and translational priority. Several well-established inducible and spontaneous animal models are available to study the onset, progression and chronicization of inflammatory joint disease, and have been instrumental in elucidating its immunopathogenesis. However, quantitative assessment of pain in animal models is technically and conceptually challenging, and it is only in recent years that inflammatory arthritis models have begun to be utilized systematically in experimental pain studies using behavioral and neurophysiological approaches to characterize acute and chronic pain stages. This article aims primarily to provide clinical and experimental rheumatologists with an overview of current animal models of arthritis pain, and to summarize emerging findings, challenges and unanswered questions in the field.

Understanding the Molecular Mechanisms Underlying the Pathogenesis of Arthritis Pain Using Animal Models

“…Although biological disease-modifying anti-rheumatic drugs (DMARDs) have revolutionized disease control and long-term outcomes of RA, substantial numbers of patients still suffer from pain despite low disease activity. The use of biological DMARDs has provided new insights into the unique qualities of pain manifestations independent of inflammation in RA [134]. The blockade of TNF-α improves pain faster than the resolution of inflammation or tissue damage, indicating a direct role for TNF-α in nociceptor sensitization pathways [135].…”

“…The K/BxN model exhibits persistent pain with mechanical hypersensitivity, which does not return to baseline levels during disease progression and outlasts inflammation [155]. Table 2 briefly summarizes the pathology and pain behaviors reported in RA models [134,137,[153][154][155][156][157][158][159][160][161][162][163][164][165][166][167]. CIA, collagen-induced arthritis; CAIA, collagen antibody-induced arthritis; AIA, antigen-induced arthritis; TNF-Tg, tumor necrosis factor transgene; IL-1RA-/-, interleukin-1 receptor antagonist knockout; CII, collagen type II; Ab, antibody; mBSA, methylated bovine serum albumin; GPI, glucose-6-phosphateisomerase; hTNF, human tumor necrosis factor; RA, rheumatoid arthritis; d, day; wk, week(s); Cat S, cathepsin S; FKN, fractalkine; TLR-4, toll-like receptor 4; IL-1RI, interleukin-1 receptor type I; pCREB, phospho-CREB.…”

“…Inflammation and suppression of pain-related spontaneous behaviors, such as locomotor activity, operant responses, and place avoidance, are strongly correlated in rapid-onset models of arthritis [134]. However, the more slowly progressing K/BxN mouse strain shows a significant delay between peak clinical progression and decreased mobility [178].…”

Imaging and Methotrexate Response Monitoring of Systemic Inflammation in Arthritic Rats Employing the Macrophage PET Tracer [18F]Fluoro-PEG-Folate

“…Many experimental animal models have been exploited to unravel the pathophysiology of inflammatory arthritis [ 7 – 12 ]. However, in most of these studies the primary research focus was on disease pathways and immune cells of the synovium rather than extra-articular manifestations.…”

Therapeutic Effect of Exogenous Truncated IK Protein in Inflammatory Arthritis

“…These results indicate that the exogenous tIK protein produced using an insect cell culture expression system has the potential to be used as an arthritis therapy. Considering the disease model, it has been reported that the CAIA model is less dependent on B and T cells than the CIA model [ 28 ], although some reports have indicated that T cells are involved in the development of inflammatory arthritis in the CAIA model [ 29 ]. Therefore, our disease model (CAIA) has limitations in testing the effects of tIK protein, which have been previously reported as the suppression of Th17 cell differentiation and macrophage activation [ 11 ].…”