Recent research has identified biological reasons for joint pain in arthritis:
- Interleukin-6, a pro-inflammatory cytokine released both locally at the joint and in the spinal cord, consequently plays a role in the widespread nature of the pain via its role in central sensitisation.
- Sprouting of sensory and sympathetic fibres at the joint may well have a role in sensitisation
- Angiogenesis, the growth of new blood vessels, at the joint, perhaps having a role in inflammation
Some of this may sound familiar. IL-6 is known to play a role in the spinal cord following nerve injury, sprouting of the sympathetic fibres at the DRG and in tendinopathy, and angiogenesis also seen in tendinopathy. All are clearly responses by the body and are involved in pain–remembering that pain is a brain experience 100% of the time of course.
Spinal interleukin-6 is an amplifier of arthritic pain (Vazquez et al. 2011)
Significant joint pain is usually widespread beyond the afflicted joint which results from the sensitization of nociceptive neurons in the central nervous system (central sensitization). In the present study we explored (a) whether the proinflammatory cytokine interleukin-6 (IL-6) in the joint induces central sensitization, (b) whether joint inflammation causes IL-6 release in the spinal cord, and (c) whether spinal IL-6 contributes to central sensitization.
In anesthetized rats electrophysiological recordings were made from spinal cord neurons with sensory input from the knee joint. Neuronal responses to mechanical stimulation of the knee and the leg were monitored. IL-6 and its soluble receptor sIL-6R were applied to the knee joint or the spinal cord. Spinal release of IL-6 was measured by ELISA. Sgp130 which neutralizes IL-6/sIL-6R was spinally applied during development of joint inflammation or during established inflammation.
A single injection of IL-6/sIL-6R into the knee joint as well as spinal application of IL-6/sIL-6R significantly increased the responses of spinal neurons to mechanical stimulation of the knee and ankle joint, i.e. induced central sensitization. Spinally applied sgp130 attenuated this IL-6 effect. Development of knee inflammation caused spinal release of IL-6. Spinal application of spg130 attenuated the development of inflammation-evoked central sensitization but did not reverse it.
Not only IL-6 in the joint is involved in the generation of joint pain but also IL-6 which is released in the spinal cord. Spinal IL-6 contributes to central sensitization and thus promotes the widespread hyperalgesia in the course of joint disease.
Neuroplasticity of sensory and sympathetic nerve fibers in the painful arthritic joint (Ghilardi et al. 2011)
Many forms of arthritis are accompanied by significant chronic joint pain. Here we studied whether there is significant sprouting of sensory and sympathetic nerve fibers in the painful arthritic knee joint and whether nerve growth factor (NGF) drives this pathological reorganization.
A painful arthritic knee joint was produced by injection of complete Freund’s adjuvant (CFA) into the knee joint of young adult mice. CFA-injected mice were then treated systemically with vehicle or anti-NGF antibody. Pain behaviors were assessed and at 28 days following the initial CFA injection, the knee joints were processed for immunohistochemistry using antibodies raised against calcitonin gene-related peptide (CGRP; sensory nerve fibers), neurofilament 200 kDa (NF200; sensory nerve fibers), growth associated protein-43 (GAP43; sprouted nerve fibers), tyrosine hydroxylase (TH; sympathetic nerve fibers), CD31 (endothelial cells) or CD68 (monocytes/macrophages).
In CFA-injected mice, but not vehicle-injected mice, there was a significant increase in the density of CD68+ macrophages, CD31+ blood vessels, CGRP+, NF200+, GAP43+, and TH+ nerve fibers in the synovium as well as joint pain-related behaviors. Administration of anti-NGF reduced these pain-related behaviors and the ectopic sprouting of nerve fibers, but had no significant effect on the increase in density of CD31+ blood vessels or CD68+ macrophages.
Ectopic sprouting of sensory and sympathetic nerve fibers occurs in the painful arthritic joint and may be involved in the generation and maintenance of arthritic pain.
Contributions of angiogenesis to inflammation, joint damage, and pain in a rat model of osteoarthritis (Ashraf et al. 2011)
To determine the contributions of angiogenesis to inflammation, joint damage, and pain behavior in a rat meniscal transection model of osteoarthritis (OA).
OA was induced in male Lewis rats (n = 8 per group) by meniscal transection. Animals were orally dosed with dexamethasone (0.1 mg/kg/day), indomethacin (2 mg/kg/day), or the specific angiogenesis inhibitor PPI-2458 (5 mg/kg every other day). Controls consisted of naive and vehicle-treated rats. Synovial inflammation was measured as the macrophage fractional area (expressed as the percentage), thickness of the synovial lining, and joint swelling. Synovial angiogenesis was measured using the endothelial cell proliferation index and vascular density. Channels positive for vessels at the osteochondral junction were assessed (osteochondral angiogenesis). Medial tibial plateaus were assessed for chondropathy, osteophytosis, and channels crossing the osteochondral junction. Pain behavior was measured as weight-bearing asymmetry.
Dexamethasone and indomethacin each reduced pain behavior, synovial inflammation, and synovial angiogenesis 35 days after meniscal transection. Dexamethasone reduced, but indomethacin had no significant effect on, the total joint damage score. PPI-2458 treatment reduced synovial and osteochondral angiogenesis, synovial inflammation, joint damage, and pain behavior.
Our findings indicate that synovial inflammation and joint damage are closely associated with pain behavior in the meniscal transection model of OA. Inhibition of angiogenesis may reduce pain behavior both by reducing synovitis and by preventing structural change. Targeting angiogenesis could therefore prove useful in reducing pain and structural damage in OA.