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.

Central nervous system (CNS) pericytes regulate critical functions of the neurovascular unit in health and disease. CNS pericytes are an attractive pharmacological target for their position within the neurovasculature and for their role in neuroinflammation. Whether the function of CNS pericytes also affects pain states and nociceptive mechanisms is currently not understood. Could it be that pericytes hold the key to pain associated with CNS blood vessel dysfunction? This article reviews recent findings on the important physiological functions of CNS pericytes and highlights how these neurovascular functions could be linked to pain states.

Pericytes play key roles in pathological processes associated with chronic pain. We propose that pericytes may be a therapeutic target for painful diseases that have associated neural vascular dysfunction. Given the paucity of new pharmacotherapies for chronic pain conditions, we hope that this review inspires researchers to unearth the potential role(s) of pericytes in chronic pain sowing the seeds for future new chronic pain therapies.