Sensory neuronal sensitisation occurs through HMGB-1/RAGE and TRPV1 in high glucose conditions

Bestall, S.M. and Hulse, R.P. and Blackley, Z. and Swift, M. and Ved, N. and Paton, K. and Beazley-Long, N. and Bates, D.O. and Donaldson, L.F. (2018) Sensory neuronal sensitisation occurs through HMGB-1/RAGE and TRPV1 in high glucose conditions. Journal of Cell Science . jcs.215939/1-jcs.215939/45. ISSN 1477-9137

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Abstract

Many potential causes for painful diabetic neuropathy have been proposed including actions of cytokines and growth factors. High mobility group protein B1 (HMGB1) is a RAGE agonist, increased in diabetes, that contributes to pain by modulating peripheral inflammatory responses. HMGB1 enhances nociceptive behaviour in naïve animals through an unknown mechanism. We tested the hypothesis that HMGB1 causes pain through direct neuronal activation of RAGE and alteration of nociceptive neuronal responsiveness. HMGB1 and RAGE expression were increased in skin and primary sensory (DRG) neurons of diabetic rats at times when pain behaviour was enhanced. Agonist-evoked TRPV1-mediated calcium responses increased in cultured DRG neurons from diabetic rats and in neurons from naïve rats exposed to high glucose concentrations. HMGB1-mediated increases in TRPV1-evoked calcium responses in DRG neurons were RAGE and PKC-dependent, and this was blocked by co-administration of the growth factor splice variant, VEGF-A165b. Pain behaviour and DRG RAGE expression increases were blocked by VEGF-A165b treatment of diabetic rats in vivo. HMGB-1-RAGE activation sensitizes DRG neurons in vitro. VEGF-A165b blocks HMGB-1/RAGE DRG activation, which may contribute to its analgesic properties in vivo.

Item Type: Article
RIS ID: https://nottingham-repository.worktribe.com/output/939740
Keywords: HMGB1; RAGE; Nociceptor; Sensitization
Schools/Departments: University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Medicine
University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Life Sciences
Identification Number: https://doi.org/10.1242/jcs.215939
Depositing User: Eprints, Support
Date Deposited: 25 Jul 2018 10:29
Last Modified: 04 May 2020 19:41
URI: http://eprints.nottingham.ac.uk/id/eprint/53133

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