Dysregulation of EAAT2 and VGLUT2 spinal glutamate transports via histone deacetylase 2 (HDAC2) contributes to paclitaxel-induced painful neuropathy

Effective treatments for chemotherapy-induced peripheral neuropathy (CIPN) remain unavailable. Given the significance of spinal cord glutamate transporters in neuronal plasticity and central sensitization, this study investigated the role of excitatory amino acid transporter 2 (EAAT2) and vesicular-glutamate transporter 2 (VGLUT2) in the development of paclitaxel-induced painful neuropathy. Paclitaxel (2 mg/kg, i.p., cumulative dose 8mg/kg) induced long-lasting mechanical allodynia (> 28days) with increased glutamate concentration and decreased EAAT2 expression with no changes in GABA/glycine or VGAT (vesicular GABA transporter) in rat spinal dorsal horn. VGLUT2 expression was upregulated and co-expressed with enhanced synaptophysin, characterizing nociceptive afferent sprouting and new synapse formation of glutamatergic neurons in the spinal cord dorsal horn. HDAC2 and transcription factor YY1 were also upregulated, and their interaction and co-localization were confirmed following paclitaxel treatment using co-immunoprecipitation (Co-IP). Inhibition or knockdown of HDAC2 expression by valproic acid (VPA), BRD6688 or HDAC2 siRNA (small interfering RNA) not only attenuated paclitaxel-induced mechanical allodynia but also suppressed HDAC2 upregulation, glutamate accumulation and the corresponding changes in EAAT2/VGLUT/synaptophysin expression and HDAC2/YY1 interaction. These findings indicate that loss of the balance between glutamate release and reuptake due to dysregulation EAAT2/VGLUT2/synaptophysin cascade in the spinal dorsal horn plays an important role in the development of paclitaxel-induced neuropathic pain. HDAC2/YY1 interaction as a complex appears essential in regulating this pathway, which can potentially be a therapeutic target to relieve CIPN by reversing central sensitization of spinal nociceptive neurons.