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

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 (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 Ca2+ 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 Ca2+ 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 the DRG RAGE expression increases were blocked by VEGF-A165b treatment of diabetic rats in vivo. Hence, we conclude that HMGB1–RAGE activation sensitises DRG neurons in vitro, and that VEGF-A165b blocks HMGB-1–RAGE DRG activation, which may contribute to its analgesic properties in vivo.

12(S)-HETE mediates diabetes-induced endothelial dysfunction by activating intracellular endothelial cell TRPV1

“…Under high-glucose conditions, TRPV1 expression in endothelial cells was not affected. Contrary to possible desensitization, high-glucose conditions are reported to rather sensitize TRPV1, resulting in increased agonist-evoked calcium responses in diabetes (41,42). In dorsal root ganglia, increased TRPV1 sensitivity is suggested to link to early painful diabetic neuropathy (43), further supporting the assumption that TRPV1 signaling is not compromised under diabetic conditions.…”

Long-Term Diabetic Microenvironment Augments the Decay Rate of Capsaicin-Induced Currents in Mouse Dorsal Root Ganglion Neurons

“…Therefore, we cannot exclude that our differing observations may be due to animal age. Moreover, ligands that can accompany diabetic conditions and activate RAGE, such as the inflammatory cytokine high-mobility group box-protein 1 (HMGB1, also known as amphoterin) and methylglyoxal, may contribute to pain behavior in diabetic neuropathy via TRPV1 or transient receptor potential ankyrin 1 (TRPA1)-dependent mechanisms [ 31 , 32 ].…”

Hypoxia induced carbonic anhydrase mediated dorsal horn sensory neuron activation and induction of neuropathic pain

“…vF filaments of increasing diameter were applied (a maximum of five seconds or until paw withdrawal), with each vF filament applied a total of 5 times to generate force response curves. Withdrawal frequencies of 50% at each weight was used to determine the mechanical withdrawal threshold (g) (21). The Hargreaves test was performed to measure thermal nociceptive behaviour (22).…”