Poly-(ADP-ribose) polymerase 1-modulated production of CXCL1 in the dorsal root ganglion and spinal dorsal horn exacerbated inflammatory pain in rats

Poly (ADP-ribose) polymerase 1 (PARP-1) serves as a transcriptional co-regulator and has been playing an important role in various inflammatory diseases. In the present study, we investigated the role and underlying mechanisms of action of PARP-1 in inflammatory pain. Intraplantar injection of complete Freund's Adjuvant (CFA) was administered to the rats to induce inflammatory pain. Immunofluorescence, Western blotting, co-immunoprecipitation, and chromatin immunoprecipitation-quantitative polymerase chain reaction were performed to investigate the underlying mechanisms. Our results showed that CFA injection led to an increase in the production and activation of PARP-1 in both the L4/5 dorsal root ganglions (DRGs) and the spinal dorsal horn. Repeated intrathecal injections of Tiq-A or 5-AIQ, two specific inhibitors of PARP-1, and microinjections of AAV-PARP-1 shRNA into the L5 DRG or L5 spinal dorsal horn partially prevented the development of inflammatory pain. The established inflammatory pain was attenuated by a single bolus of intrathecal injection of Tiq-A or 5-AIQ on day 7 after the CFA injection. The CFA-induced mechanical allodynia and thermal hyperalgesia in female rats were alleviated by repeated intrathecal injections of Tiq-A. Moreover, repeated intrathecal injections of 5-AIQ inhibited the binding of NF-κB with CXCL1 promoter and reduced the production of CXCL1 in both the L4/5 DRGs and L4-6 spinal dorsal horns following CFA injection. Collectively, our results indicate that CFA-induced upregulation of PARP-1 by promoting CXCL1 expression in the DRG and probably in the spinal dorsal horn contributes to the pathogenesis of inflammatory pain. Thus, PARP-1 may be a potential pharmaceutical target for the treatment of inflammatory pain.

CXCL1; Dorsal root ganglion; Epigenetics; Inflammatory pain; Poly-(ADP-ribose) polymerase 1; Spinal cord.