In these studies we tested the hypotheses that: (1) hyperglycaemia is associated with increased peripheral HMGB1 expression in diabetic rats when mechanical and thermal hypersensitivity is present, (2) HMGB1 sensitises neurons through actions on TRPV1, (3) high-glucose conditions alter TRPV1-mediated signalling in sensory neurons through an HMGB1–RAGE–PKC-dependent mechanism, and (4) that the effects of HMGB1 on sensory neurons can be reversed by VEGF-A165b treatment. Here, TRPV1 is linked to Hyperglycemia.