Effect of lappaconitine on neuropathic pain mediated by P2X3 receptor in rat dorsal root ganglion

ATP facilitates initiation and transmission of the neuropathic pain at the dorsal root ganglion (DRG) level via the P2X receptors, especially the subtype P2X3. Lappaconitine (LA) is an active principle isolated from Chinese herbal medicine and possesses analgesic effect. The aim of this study was to investigate the effect of LA on chronic constriction injury (CCI)-induced neuropathic pain mediated by P2X3 receptor in the DRG neurons. In the presence of CCI and/or LA, the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were measured and P2X3 receptor expression in the DRG neurons was evaluated by immunohistochemistry and Western blotting. Following intrathecal administration of P2X3 receptor oligonucleotide, the effect of LA on pain thresholds was assessed. Furthermore, the effect of LA on the P2X3 receptor agonists ATP- and α,β-meATP-induced inward currents (IATP and Iα,β-meATP) in the acutely dissociated rat DRG neurons was investigated by whole cell patch-clamp. The results included: (1) There showed reduction of pain thresholds, enhancement of IATP and Iα,β-meATP and up-regulation of P2X3 receptor expression in rat DRG neurons when neuropathic pain occurred. (2) In the presence of LA, the decreased pain thresholds, the up-regulated P2X3 receptor expression and the enhanced IATP and Iα,β-meATP were reversible in the CCI rats. (3) The down-regulated P2X3 receptor expression with pretreatment of P2X3 receptor antisense oligonucleotide significantly attenuated the analgesic effect of LA. These results indicate that the analgesic effect of LA involves decrease of expression and sensitization of the P2X3 receptors of the rat DRG neurons following CCI.

Research highlights
► LA inhibited CCI-induced mechanical and thermal hyperalgesia.
► LA reduced CCI-induced up-regulation of P2X3 receptor expression in DRG neurons.
► LA negatively modulated fast IATP and fast Iα,β-meATP in the CCI rat DRG neurons.
► Following P2X3 receptor A-ODN treatment, the analgesic effect of LA was inhibited.
► This study contributed to understanding of the mechanism of LA analgesia.