Abstract
Chronic pain can develop in response to conditions such as inflammatory arthritis. The central mechanisms underlying the development and maintenance of chronic pain in humans are not well elucidated although there is evidence for a role of microglia and astrocytes. However in pre-clinical models of pain, including models of inflammatory arthritis, there is a wealth of evidence indicating roles for pathological glial reactivity within the CNS. In the spinal dorsal horn of rats with painful inflammatory arthritis we found both a significant increase in CD11b+ microglia-like cells and GFAP+ astrocytes associated with blood vessels, and the number of activated blood vessels expressing the adhesion molecule ICAM-1, indicating potential glio-vascular activation. Using pharmacological interventions targeting VEGFR2 in arthritic rats, to inhibit endothelial cell activation, the number of dorsal horn ICAM-1+ blood vessels, CD11b+ microglia and the development of secondary mechanical allodynia, an indicator of central sensitization, were all prevented. Targeting endothelial VEGFR2 by inducible Tie2-specific VEGFR2 knock-out also prevented secondary allodynia in mice and glio-vascular activation in the dorsal horn in response to inflammatory arthritis. Inhibition of VEGFR2 in vitro significantly blocked ICAM-1-dependent monocyte adhesion to brain microvascular endothelial cells, when stimulated with inflammatory mediators TNF-α and VEGF-A165a. Taken together our findings suggest that a novel VEGFR2-mediated spinal cord glio-vascular mechanism may promote peripheral CD11b+ circulating cell transmigration into the CNS parenchyma and contribute to the development of chronic pain in inflammatory arthritis. We hypothesise that preventing this glio-vascular activation and circulating cell translocation into the spinal cord could be a new therapeutic strategy for pain caused by rheumatoid arthritis.
Highlights
Pain experienced by rheumatoid arthritis patients is chronic, debilitating, and can persist despite adequate control of inflammation (Taylor et al, 2010; Heiberg and Kvien, 2002; McWilliams and Walsh, 2016)
In many chronic painful diseases and animal models reactive astrocytes and microglia in the dorsal horn contribute to central sensitization and the generation of pain (Taylor et al, 2017; Mifflin and Kerr, 2017), we investigated changes in dorsal horn glial fibrillary acidic protein (GFAP, reactive astrocytes) and CD11b expression at the spinal level corresponding to sensory input from the site of secondary sensitivity
Eight days after intra-articular Complete Freund’s adjuvant (CFA), glial fibrillary acid protein (GFAP) expression was more prominent than in non-inflamed controls Fig. 1e-f), and there was a small number of CD11b+ cells, which were not observed in non-inflamed controls
Summary
Pain experienced by rheumatoid arthritis patients is chronic, debilitating, and can persist despite adequate control of inflammation (Taylor et al, 2010; Heiberg and Kvien, 2002; McWilliams and Walsh, 2016). The mechanisms that drive pain in rheumatoid arthritis are complex and involve peripheral inflammation, joint damage, peripheral nociceptive processes and central sensitization, the latter being thought to underpin chronic pain. Because of this complex aetiology, patients can experience unprovoked pain in. Current therapies for rheumatoid arthritis aim to control systemic and joint-associated inflammation and have a degree of success (Walsh and McWilliams, 2012), but often fail to control pain. There still remains, a pressing need for better control for the pain that persists in the face of optimal inflammatory control (McWilliams and Walsh, 2016; Emery, 2012)
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