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

Bestall, Samuel M.; Hulse, Richard P.; Blackley, Zoe; Swift, Matthew; Ved, Nikita; Paton, Kenneth; Beazley-Long, Nicholas; Bates, David O.; Donaldson, Lucy F.

Authors

Samuel M. Bestall

Richard P. Hulse

Zoe Blackley

Matthew Swift

Nikita Ved

Kenneth Paton

Nicholas Beazley-Long

LUCY DONALDSON Lucy.Donaldson@nottingham.ac.uk
Professor of Sensory Physiology



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.

Citation

Bestall, S. M., Hulse, R. P., Blackley, Z., Swift, M., Ved, N., Paton, K., …Donaldson, L. F. (in press). Sensory neuronal sensitisation occurs through HMGB-1/RAGE and TRPV1 in high glucose conditions. Journal of Cell Science, https://doi.org/10.1242/jcs.215939

Journal Article Type Article
Acceptance Date Jun 14, 2018
Online Publication Date Jun 21, 2018
Deposit Date Jul 25, 2018
Publicly Available Date Jul 25, 2018
Journal Journal of Cell Science
Print ISSN 0021-9533
Electronic ISSN 1477-9137
Publisher Company of Biologists
Peer Reviewed Peer Reviewed
Article Number jcs.215939
DOI https://doi.org/10.1242/jcs.215939
Keywords HMGB1; RAGE; Nociceptor; Sensitization
Public URL http://eprints.nottingham.ac.uk/id/eprint/53133
Publisher URL http://jcs.biologists.org/content/early/2018/06/13/jcs.215939
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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