Methylglyoxal alters C-fibre activity-dependent slowing and induces heat hyperalgesia in a sex-dependent manner, in rats

Introduction: 1.8 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. Objective: Explore 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. Results: Compound action potential recording of isolated dorsal roots incubated with methylglyoxal (100 µM, 3 hours) 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 µM/1 mM, 10 minutes) did not modify C-fibre ADS. Systemic methylglyoxal administration (5 μg, 3 h 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. Conclusion: We 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 after systemic methylglyoxal treatment.