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Spontaneous and Evoked Measures of Pain in Murine Models of Monoarticular Knee Pain

Pain is the main cause of disability from arthritis. There is currently an unmet need for adequate treatments for arthritis pain. Pre-clinical models are ...

University of Minnesota

VA Health Care Center

During inflammatory processes, monocytes leave the blood stream at increased rates and enter inflammation tissue, where they undergo phenotypic transformation to mature macrophages with enhanced phagocytic activity. alpha-Actinin, a cytoskeletal protein, is present in focal adhesion complexes and left in the microenvironment as a result of cell movement. Mactinin, a 31 kDa amino-terminal fragment of alpha-actinin, is generated by the degradation of extracellular alpha-actinin by monocyte-secreted urokinase. We have previously demonstrated that mactinin promotes monocyte/macrophage maturation. We now report that 0.5-10 nM mactinin has significant chemotactic activity for monocytes. Mactinin seems to be present in inflammatory arthritis synovial fluid, because affinity-purified antisera reacted with a protein of the expected molecular mass in various types of arthritis fluids that were immunoaffinity-purified and subjected to Western analysis. Thus, six of seven samples from patients with psoriatic arthritis, reactive arthritis, gout, or ankylosing spondylitis contained mactinin at levels that are active in vitro. Initially, mactinin was not found in affinity-purified rheumatoid arthritis samples. However, it was detectable after the dissociation of immune complexes, suggesting that it was complexed to anti-microfilament auto-antibodies. In addition, mactinin was found in the lavage fluid from the arthritic knee joints of rabbits with antigen-induced arthritis and was absent from the contralateral control knee fluids. We conclude that mactinin is present in several types of inflammatory arthritis and might modulate mononuclear phagocyte response to inflammation.

Mactinin: a modulator of the monocyte response to inflammation.

A recent survey of medical and surgical residents in the United States suggested that our current training of physicians may be inadequate to meet the increasing demand for diagnosis and treatment of musculoskeletal disorders. In response, we developed an integrated, multidisciplinary course to teach knowledge and skills related to musculoskeletal disease to second-year medical students. A three-year prospective outcomes study was conducted to evaluate the new course.

Development and evaluation of an integrated musculoskeletal disease course for medical students.

We report the use of intra-articular Botulinum toxin A in two RA patients with persistently painful monoarthritis in ankle/feet joints. Both patients had monarticular pain despite a good response of all other joints to a combination therapy that included anti-tumor necrosis factor therapy. Both patients had failed intra-articular corticosteroid injections and declined surgical options. After a single, "off-label", intra-articular injection of Botulinum toxin A into the right ankle (100 unit) and left first metatarsophalangeal joint (25 unit), respectively, pain and function improved significantly (> or =40%) in both patients. Durable response with improvement of pain and function lasting 15-18 months was noted (follow-up continuing). Ankle joint swelling resolved by 15 months and MTP joint swelling by one month. Intra-articular BoNT/A may be an additional therapeutic option in RA patients with persistent monoarthritis. A randomized study is underway to confirm these findings.

Intra-articular botulinum toxin A as an adjunctive therapy for refractory joint pain in patients with rheumatoid arthritis receiving biologics: a report of two cases.

Repeat injections of intra-articular botulinum toxin a for the treatment of chronic arthritis joint pain.

To assess short-term efficacy of single intraarticular botulinum toxin (IA-BoNT/A) injection in patients with chronically painful total knee arthroplasty (TKA) in a randomized, placebo-controlled, triple-blind study.

Intraarticular botulinum toxin A for refractory painful total knee arthroplasty: a randomized controlled trial.

To evaluate the analgesic effectiveness of intra-articular botulinum toxin Type B (BoNT/B) in a murine model of chronic degenerative arthritis pain.

Analgesic effects of intra-articular botulinum toxin Type B in a murine model of chronic degenerative knee arthritis pain.

Carrageenan-induced arthritis is a painful acute arthritis model that is simple to induce, with peak pain and inflammation occurring at about 3 hours. This arthritis model can be evaluated using semiquantitative evoked or non-evoked pain scoring systems. These measures are subjective and are often time- and labor-intensive. It would be beneficial to utilize quantitative, nonsubjective evaluations of pain with rapid assessment tools. We sought to compare the DigiGait™ and TreadScan™ systems and to validate the two gait analysis platforms for detection of carrageenan-induced monoarthritis pain and analgesic response through changes in gait behavior.

A comparison of DigiGait™ and TreadScan™ imaging systems: assessment of pain using gait analysis in murine monoarthritis.

Arthritis is the most common cause of disability in the US, and the primary manifestation of arthritis is joint pain that leads to progressive physical limitation, disability, morbidity, and increased health care utilization. Capsaicin (CAP) is a vanilloid agonist that causes substance P depletion by interacting with vanilloid receptor transient receptor potential V1 on small unmyelinated C fibers. It has been used topically for analgesia in osteoarthritis with variable success. Resiniferatoxin (RTX) is an ultra potent CAP analog. The aim of this study was to measure the analgesic effects of intra-articular (IA) administration of CAP and RTX in experimental acute inflammatory arthritis in mice. Evoked pain score (EPS) and a dynamic weight bearing (DWB) device were used to measure nociceptive behaviors in a murine model of acute inflammatory monoarthritis. A total of 56 C57B16 male mice underwent EPS and DWB testing - 24 nonarthritic controls and 32 mice with carrageenan-induced arthritis. The effects of pretreatment with 0.1% CAP, 0.0003% RTX, or 0.001% RTX were measured. Nociception was reproducibly demonstrated by increased EPS and reduced DWB measures in the affected limb of arthritic mice. Pretreatment with 0.001% RTX resulted in statistically significant improvement in EPS and DWB measures when compared with those observed in carrageenan-induced arthritis animals. Pretreatment with IA 0.0003% RTX and IA 0.01% CAP resulted in improvement in some but not all of these measures. The remaining 24 mice underwent evaluation following treatment with 0.1% CAP, 0.0003% RTX, or 0.001% RTX, and the results obtained were similar to that of naïve, nonarthritic mice. 

The effect of intra-articular vanilloid receptor agonists on pain behavior measures in a murine model of acute monoarthritis.

Capsaicin (CAP) and Resiniferatoxin (RTX) are vanilloid receptor agonists that can normalize Evoked Pain Scores (EPS) and Automated Dynamic Weight Bearing (ADWB) measures in murine acute inflammatory arthritis when given by intra-articular (IA) injection. To determine whether these vanilloid receptor agonists have benefit in Complete Freund's Adjuvant (CFA) induced chronic inflammatory arthritis pain, we measured changes in ADWB and EPS in arthritic mice with and without treatment with IA CAP and RTX.

The Effect of Treatment with Resiniferatoxin and Capsaicin on Dynamic Weight Bearing Measures and Evoked Pain Responses in a Chronic Inflammatory Arthritis Murine Model.

We previously reported the efficacy of intraarticular (IA) rimabotulinumtoxinB (BoNT/B) in a murine model of chronic degenerative arthritis pain. This study aimed to measure the analgesic effects of onabotulinumtoxinA (BoNT/A) on collagenase induced chronic degenerative arthritis joint pain.

Maren Mahowald

Department of Medicine

University of Minnesota

Spontaneous and Evoked Measures of Pain in Murine Models of Monoarticular Knee Pain

Maren Mahowald

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Medicine

University of Minnesota

Spontaneous and Evoked Measures of Pain in Murine Models of Monoarticular Knee Pain

Department of Medicine