Methylglyoxal alters C-fibre Activity-Dependent Slowing and Induces Heat Hyperalgesia in a Sex-Dependent Manner

Abstract

IntroductionRaised plasma levels of the glycolytic metabolite methylglyoxal are associated with pain symptoms in patients with diabetic neuropathy. Methylglyoxal can regulate the function of NaV1.7 and NaV1.8 ion channels that are involved in the phenomenon of activity-dependent slowing (ADS) in C-fibre nociceptors. C-fibre ADS differs between the sexes and can regulate spinal network function. ObjectiveExplore the impact of methylglyoxal upon C-fibre ADS and pain sensitivity in both sexes. In addition, investigate the influence of ADS upon the processing of C-fibre inputs, in noxious heat responsive spinal neurons. ResultsCompound action potential recording of isolated dorsal roots incubated with methylglyoxal (100{micro}M, 3 hr) revealed a sex-dependent impact upon C-fibre ADS. In male roots, C-fibre ADS was reduced whereas in female roots it was increased. Acute methylglyoxal application (100{micro}M/1mM, 10 min) did not modify C-fibre ADS. Systemic methylglyoxal administration (5g, 3h prior) induced heat hyperalgesia in male but not female juvenile rats. Patch-clamp recording in spinal slices with attached dorsal roots revealed that length-dependent manipulation of ADS altered action potential firing to stimulus trains in noxious heat responsive Fos-EGFP+ spinal neurons. ConclusionWe propose that methylglyoxal sex-dependent regulation of C-fibre ADS influences the spinal processing of noxious heat inputs that may contribute to the male specific induction of heat hyperalgesia following systemic methylglyoxal treatment. SummaryMethylglyoxal, implicated in painful diabetic neuropathy, sex-dependently alters C-fibre ADS, potentially influencing spinal processing of noxious heat to drive heat hyperalgesia in males only.