Abstract
ABSTRACTMany 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.
Highlights
Diabetic neuropathy affects up to 50% of diabetic patients (Obrosova, 2009), and results from changes in the peripheral sensory nerve microenvironment due to microvasculopathy and direct actions of high glucose on peripheral sensory neurons
receptor for AGE (RAGE) expression is mediated by a positive feedback mechanism upon RAGE activation (Li and Schmidt, 1997), and we determined whether there was any change in RAGE expression in sensory neurons in diabetic rats
The proportion of dorsal root ganglia (DRG) neurons positive for RAGE expression was increased in diabetic rats compared to naïve rats, as previously reported (Zochodne, 2014), and this was unaffected by VEGF-A165b treatment (Fig. 2B)
Summary
Diabetic neuropathy affects up to 50% of diabetic patients (Obrosova, 2009), and results from changes in the peripheral sensory nerve microenvironment due to microvasculopathy and direct actions of high glucose on peripheral sensory neurons. Peripheral sensory fibre damage in nerve trunks results in local inflammatory responses and the development of neuropathic pain, including symptoms of allodynia and hyperalgesia, in experimental models of diabetes and during naturally occurring diabetes (Calcutt et al, 2008). Long-standing hyperglycaemia results in the formation and accumulation of advanced glycation end products (AGEs) (Singh et al, 2014), which can activate the receptor for AGE (RAGE; known as AGER) and cause neuronal damage. RAGE expression is increased in peripheral neurons in traumatic (Allette et al, 2014) and diabetic neuropathy (Juranek et al, 2013), and RAGE neutralisation inhibits neuropathic pain (Brederson et al, 2016). The mechanism(s) of RAGE signalling on sensory neuronal sensitisation are unknown
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