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

Autor: Bestall SM; School of Life Sciences, The Medical School QMC, University of Nottingham, Nottingham NG7 2UH, UK., Hulse RP; Arthritis Research UK Pain Centre, The Medical School QMC, University of Nottingham, Nottingham NG7 2UH, UK., Blackley Z; School of Life Sciences, The Medical School QMC, University of Nottingham, Nottingham NG7 2UH, UK., Swift M; School of Life Sciences, The Medical School QMC, University of Nottingham, Nottingham NG7 2UH, UK.; Cancer Biology, School of Clinical Sciences, University of Nottingham, Nottingham NG7 2UH, UK., Ved N; Arthritis Research UK Pain Centre, The Medical School QMC, University of Nottingham, Nottingham NG7 2UH, UK.; Institute of Ophthalmology, 11-43 Bath St, London EC1V 9EL, UK., Paton K; School of Life Sciences, The Medical School QMC, University of Nottingham, Nottingham NG7 2UH, UK., Beazley-Long N; School of Life Sciences, The Medical School QMC, University of Nottingham, Nottingham NG7 2UH, UK.; Arthritis Research UK Pain Centre, The Medical School QMC, University of Nottingham, Nottingham NG7 2UH, UK., Bates DO; Cancer Biology, School of Clinical Sciences, University of Nottingham, Nottingham NG7 2UH, UK., Donaldson LF; School of Life Sciences, The Medical School QMC, University of Nottingham, Nottingham NG7 2UH, UK Lucy.Donaldson@nottingham.ac.uk.; Arthritis Research UK Pain Centre, The Medical School QMC, University of Nottingham, Nottingham NG7 2UH, UK.
Jazyk: angličtina
Zdroj: Journal of cell science [J Cell Sci] 2018 Jul 26; Vol. 131 (14). Date of Electronic Publication: 2018 Jul 26.
DOI: 10.1242/jcs.215939
Abstrakt: 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 (also known as AGER) agonist whose levels are increased in diabetes and 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 (dorsal root ganglion, DRG) neurons of diabetic rats at times when pain behaviour was enhanced. Agonist-evoked TRPV1-mediated Ca 2+ 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 Ca 2+ responses in DRG neurons were RAGE- and PKC-dependent, and this was blocked by co-administration of the growth factor splice variant VEGF-A 165 b. Pain behaviour and the DRG RAGE expression increases were blocked by VEGF-A 165 b treatment of diabetic rats in vivo Hence, we conclude that HMGB1-RAGE activation sensitises DRG neurons in vitro , and that VEGF-A 165 b blocks HMGB-1-RAGE DRG activation, which may contribute to its analgesic properties in vivo .
Competing Interests: Competing interestsL.F.D. and D.O.B. are co-inventors on patents protecting alternative RNA splicing control and VEGF-A splice variants for therapeutic application in a number of different conditions. L.F.D. and D.O.B. are founder equity holders in, and consultants (both) and director (D.O.B.) to Exonate Ltd, a University of Nottingham spin-out company with a focus on development of alternative RNA splicing control for therapeutic application in a number of different conditions, including analgesia and neuroprotection (www.exonate.com). Exonate made no financial contribution to this study. The University of Nottingham also holds equity in Exonate Ltd.
(© 2018. Published by The Company of Biologists Ltd.)
Databáze: MEDLINE
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