Botz, B

Denes, A

Goebel, A

Helyes, Z

Kiss, T

Pohoczky, K

Sensi, S

Szentes, N

Tekus, V

University of Liverpool Repository

Non-inflammatory autoantibody-induced glia activation in a passive transfer-trauma mouse model of Complex Regional Pain SyndromeZsuzsanna Helyes1,3,4, Valeria Tékus1, Nikolett Szentes1, Krisztina Pohóczky1, Balint Botz1, Tamás Kiss1, Ádám Dénes2, S. Sensi5, Andreas Goebel5,6 1Department of Pharmacology and Pharmacotherapy, Medical School; János Szentágothai Research Centre &Centre for Neuroscience, University of Pécs, Pécs, Hungary2Laboratory of Molecular Neuroendocrinology, Institute of Experimental Medicine, Budapest, Hungary3PharmInVivo Ltd., Pécs, Hungary4 MTA-PTE NAP B Chronic Pain Research Group, Pécs, Hungary5Department of Translational Medicine, University of Liverpool, Liverpool, UK 6The Walton Centre NHS Foundation Trust, Liverpool, UKCRPS is one of the most severe chronic pain conditions in humans associated with limb-restricted exaggerated sensory and autonomic abnormalities after small injuries. Abnormal immune response against sensory nerve-derived antigens and complex neuro-immune interactions are suggested to be responsible for the severe, persistent pain, edema and autonomic symptoms. However, the pathophysiological mechanisms are unclear and the therapy is not satisfactory. In our passive-transfer translational mouse model, we investigated the behavioural, immunological and neurochemical changes characteristic of the disease.Small plantar skin-muscle incision was performed in female C57Bl/6 mice daily treated i.p. with purified serum-IgG of CRPS patients or healthy volunteers (n=4-4; 6 mice/group) for 3-13 days do determine duration-dependent alterations of the pathophysiological mechanisms. The mechanonociceptive threshold of the hindpaw was measured by dynamic planar aesthesiometry, volume by plethysmometry, neutrophil/macrophage myeloperoxidase activity by luminescence in vivo imaging, sensory neuropeptides and inflammatory cytokines by immunassays, glia markers in pain-related brain regions with immunochemistry.CRPS IgG significantly increased and prolonged hyperalgesia and swelling of the incised paw compared to healthy IgG. CRPS-treatment had the strongest hyperalgesia-increasing effect in the second week, when swelling resolved. Moderate, but significant myeloperoxidase activity and substance P-like immunoreactivity increases were detected in the paw of CRPS IgG-treated mice transiently on days 2 and 7 compared to healthy IgG. In contrast, the levels of calcitonin gene-related peptide and any of the 10 measured inflammatory cytokines were not altered. CRPS IgG significantly increased the density of astrocyte-related glial fibrillary acidic protein (GFAP) and microglia-staining Iba1 in L4-L5 spinal dorsal horn, periaquaductal gray and somatosensory cortex. GFAP increased in the first week both in the affected and contralateral sides, Iba1 elevated only ipsilaterally mainly later.The main symptoms of CRPS with special emphasis on hyperalgesia can be reliably transferred from patients to mice by IgG. Hyperalgesia is not parallel with edema formation and the inflammatory reaction. Therefore, peripheral inflammation does not play a crucial role in this pathological pain, but glia-mediated central sensitization is more likely to be involved. Support: KTIA_NAP_13-2014-0022 (PTE-NAP B Chronic Pain Research Group); Pain Relief Foundation; GINOP-2.3.2-15-2016-00050 – PEPSYS  

Non-inflammatory autoantibody-induced glia activation in a passive transfer-trauma mouse model of complex regional pain syndrome

http://livrepository.liverpool.ac.uk/3018830/1/AbstractNeurochemistry2017-Helyes.doc

Non-inflammatory autoantibody-induced glia activation in a passive transfer-trauma mouse model of complex regional pain syndrome

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