Sadaf Ashraf, University of Nottingham
The objective of this recent paper from Patrick W. Mantyh’s laboratory was to look at the aberrant sprouting of sensory and sympathetic nerve fibers in a rodent knee joint model of monoarthritis (Complete Freund’s Adjuvant [CFA]) and whether nerve growth factor (NGF) drives this pathological feature.
They hypothesized that following inflammatory joint injury, neuropathic factors are released which alter normal sensory and sympathetic nerves causing ectopic sprouting in normal aneural joint areas and increasing the densities of the nerves in areas that normally contain fewer nerve fibers. As a result, non-painful signals are now perceived as being painful, highlighting that severity of pain is a combination of both joint destruction and remodeling of sensory and sympathetic nerve fibers, a concept that is not fully investigated within the arthritic pain research community.
In order to investigate this hypothesis they used the CFA model of inflammatory arthritic pain, which is extensively used in the laboratory and produces many features similar to those of rheumatoid arthritis (RA) such as pannus formation. However the methods to assess pain in these animal models do not truly reflect the spontaneous pain behavior seen in arthritic patients. So question arises as to how far we can extrapolate rodent pain behavior data to model human arthritic pain characteristics.
In the study, intra-articular injection of CFA or saline control was given every 7 days over a period of 28 days in the knee joint of adult mice. Intraperitoneal administration of anti-NGF or vehicle was given before and at days 5, 10, 15 and 25 after CFA injection. Behavioral measures used were spontaneous pain (flinching), stimulus evoked pain and dynamic weight bearing. At the end of the experiment, animals were intracardially perfused and knees were post-fixed, decalcified and sectioned. Frozen sections were processed for immunohistochemistry using antibodies raised against sympathetic and sensory nerve fibers as well as macrophages and blood vessels. Computer assisted image analysis was used to quantify the densities of all of the above. Standard histology techniques were used to look at the bone histology.
The group showed that following CFA injection, there was an increase in pain behavior and synovial increase of CD68+ macrophages, CD31+ blood vessels, CGRP+ and NF200+ sensory nerves, GAP43+ sprouted nerve fibers and TH+ sympathetic nerve fibers. Following anti-NGF treatment there was a reduction in the pain behavior and nerve sprouting but not synovial macrophage infiltration or blood vessel growth. The group therefore concluded that aberrant growth of sensory and sympathetic nerve fibers occurring in the arthritic joint could contribute to arthritic pain.
This adds to the existing body of evidence implicating an important role of inflammation and NGF/TrkA pathway in arthritic pain. It is well known that due to joint injury and/or inflammation, nerves become sensitized. Loss of cartilage and the exposure of the underlying subchondral bone means that any movement would lead to bone on bone contact and hence activation of nerve fibers and the sensation of pain. The changes in the peripheral joint can lead to neurochemical and cellular changes in the spinal cord and brain (central sensitization) contributing to the experience of ongoing arthritic pain. Therefore it would have been informative if the group had addressed some of these changes occurring at the level of central sensitization, such as the up regulation of TrkA protein and/or mRNA levels for example or its effects on the membrane surface channel; TRPV1 (transient receptor potential vanilloid 1), which is well known to be an integral component of pain. Only synovial changes were addressed; examination of the organization of sympathetic and sensory nerves in the meniscus, osteochondral junction and the bone and the effects of anti-NGF treatment on these changes would have further strengthened the data.
Under the current situation where doubt hangs over the benefits of anti-NGF treatment in arthritic pain, this data strengthens the notion that NGF/TrkA pathway is crucial in the experience of arthritic pain and targeting it has a huge therapeutic value. Since this current data shows that anti-NGF treatment has no effect on synovitis and synovial blood vessel growth but blocks aberrant nerves only, it further proves the specificity of the compound.
Just this month, The Food and Drug Administration (FDA) in Washington passed a motion after 21 of its arthritis expert panel members voted unanimously that research on these nerve-blocking drugs should continue with certain safety precautions. Hence further studies like these are clearly warranted and are very beneficial in clarifying the role of NGF/TrkA in arthritic pain.
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