December 17, 2018, by hjohnson
New mechanism for the spreading of pain in inflammatory arthritis
Written by Lucy Tyler
As the home of the Arthritis Research UK Pain Centre, much of the research conducted at the University of Nottingham’s School of Life Sciences in the Queen’s Medical Centre, is based on chronic pain and how it can be treated more effectively.
Arthritis is an umbrella term for disorders of the joints, characterised by long-term pain and poor joint mobility. Rheumatoid arthritis is the most prevalent inflammatory type globally and affects approximately 1 in 50 people in the UK. People living with rheumatoid arthritis suffer spontaneous chronic pain and an increased sensitivity to painful and non-painful stimuli. The pain can spread to areas that are not directly affected by inflammation, which is known as secondary pain. Chronic pain occurs when the nervous system, including the spinal cord, becomes more responsive to stimuli but the mechanism by which it arises and is maintained (becomes chronic) is currently unknown. Chronic pain and arthritic pain are currently treated by combinations of different analgesic drugs. Rheumatoid arthritis is progressive and safety concerns regarding current treatments can lead to low dosing and poor drug effectiveness.
Many people suffering from arthritis experience pain even when the joint inflammation is controlled. Both the immune cells that reside in the nervous system and in the blood are thought to play a substantial role in establishing chronic pain, especially in arthritis. Pain is detected in the periphery and processed in the central nervous system. It is first processed in the spinal cord and then perceived in the brain. Immune cells found in the blood can only have an effect on the brain and spinal cord if they can penetrate the blood-brain barrier. The blood-brain barrier is formed by different cell-types wrapping blood vessels and preventing the leakage of cells and molecules from the blood into the brain and spinal cord. The blood vessel walls are formed by endothelial cells which are joined together by tight junctions to prevent blood contents leaking out. Other cells also have roles in regulating blood flow and forming barriers to brain and spinal cord tissue. Immune and blood vessel cells release signalling molecules called cytokines into the circulation which contribute to the blood-brain barrier becoming more permeable and cause recruitment of immune cells.
People living with rheumatoid arthritis have an increased level of a molecule important for blood vessel function in the blood. This molecule is called vascular endothelial growth factor (VEGF). Dr Nick Beazley-Long and his lab at The University of Nottingham have found that VEGF activates endothelial cells and makes the blood-brain barrier more permeable, which is a potential mechanism by which immune cells enter the nervous system and contribute to the onset of chronic pain. As a growth factor, VEGF is necessary for the maintenance and formation of blood vessels. VEGF binding at its receptors initiates a number of cellular responses. VEGF receptor 2 (VEGFR2) is the most well characterised of the 3 VEGF receptors and the team has found that blocking its function decreases secondary pain and mildly decreases joint swelling.
The team has measured how manipulation of VEGF receptor 2 changes levels of immune cells present in the spinal cord, the threshold to detect a non-painful stimulus, weight-bearing and the swelling of the knee on the side affected by inflammatory arthritis and the threshold to detect a non-painful stimulus at a site away from the inflammation on the same side (which is indicative of secondary pain). Either injecting different pharmacological blockers of VEGF receptor 2, or preventing VEGF receptor 2 expression exclusively in endothelial cells by stopping the gene expression, significantly reduced or prevented all of these parameters.
Some of the blockers cannot cross into the brain. They act exclusively on blood vessels to reduce pain. The team propose that preventing the activation of endothelial cells lining blood vessels stops the blood-brain barrier becoming more permeable and possibly prevents immune cells entering the spinal cord. Fewer cytokines are released and the pain-processing neurons in the spinal cord do not become more excited, thus acting as an effective analgesic specifically for arthritic pain.
The next steps for the research group include establishing how VEGF receptor 2 activation contributes to manifestation of chronic pain, finding a VEGF receptor 2 blocker that might clinically reduce pain in rheumatoid arthritis patients and the best method of delivering it to the site of action.
 Symmons, D., Turner, G., Webb, R., Asten, P., Barrett, E., Lunt, M., Scott, D. and Silman, A., 2002. The prevalence of rheumatoid arthritis in the United Kingdom: new estimates for a new century. Rheumatology, 41(7), pp.793-800.
 van Laar, M., Pergolizzi Jr, J.V., Mellinghoff, H.U., Merchante, I.M., Nalamachu, S., O’Brien, J., Perrot, S. and Raffa, R.B., 2012. Pain treatment in arthritis-related pain: beyond NSAIDs. The open rheumatology journal, 6, p.320.
 In rodents with inflammatory arthritis.
The full publication: Beazley-Long, N., Moss, C.E., Ashby, W.R., Bestall, S.M., Almahasneh, F., Durrant, A.M., Benest, A.V., Blackley, Z., Ballmer-Hofer, K., Hirashima, M. and Hulse, R.P., 2018. VEGFR2 promotes central endothelial activation and the spread of pain in inflammatory arthritis. Brain, behavior, and immunity.
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