VEGFR2 promotes central endothelial activation and the spread of pain in inflammatory arthritis.

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.

Sensory nerves have altered function contralateral to a monoarthritis and may contribute to the symmetrical spread of inflammation.

Rheumatoid arthritis (RA) and rat models of RA exhibit symmetrical mirror-image spread. Many studies have sought to understand the underlying mechanisms and have reported contralateral effects that are manifested in many different forms. It is now well accepted that neurogenic mechanisms contribute to the symmetrical spread of inflammation. However, very few investigators have directly assessed changes in contralateral nerve function and there is a paucity of data. In the present study our aim was to investigate whether there are changes, in particular in the nervous system but also in the vascular system contralateral to an inflamed rat knee joint, that might precede overt inflammation and symmetrical spread. Three to five days following Complete Freund's Adjuvant (CFA) injection we found spontaneous antidromic (away from the CNS) activity in the homologous sensory nerve contralateral to the inflamed joint. Antidromic activity of this nature is known to result in the peripheral release of pro-inflammatory and vasoactive neuropeptides. Importantly, this activity was modulated by systemic analgesic treatment. Furthermore, levels of Evans blue dye extravasation were significantly increased in the joint contralateral to inflammation, indicating altered vascular function. These data suggest that contralateral increases in sensory neural activity and vascular function may account for the symmetrical spread of RA, and that early analgesic treatment may prevent or delay the spread of this debilitating disease.