Wnt5a mediates chronic post-thoracotomy pain by regulating non-canonical pathways, nerve regeneration, and inflammation in rats

摘要

As well-characterized ligands involved in neurogenesis, Wnts are emerging as promising targets in pain pathogenesis. Our previous pilot study showed that intrathecal inhibition of Wnt5a, but not Wnts, relieves chronic post-thoracotomy pain (CPTP) in rats. In the present study, we aimed to further explore the regulatory mechanism of Wnt5a in CPTP development. Increased protein levels of Wnt5a, transmembrane receptor Ror2, and activated non-canonical Wnt pathway members were found in the thoracic dorsal root ganglions from postoperative day (POD) 7 to POD 21. However, the levels of canonical Wnt pathway members showed no change by reverse transcriptase-PCR. In addition, elevated nerve regeneration, activated pro-inflammatory factors, and glial cells were detected from POD 7 to POD 21. Furthermore, intrathecal Wnt5a blockade during the early phase (POD 0 to POD 9) significantly increased the pain threshold, and intervention in the late phase (POD 14 to POD 16) alleviated pain; however, the analgesic response was not as effective as that in the early phase. Additionally, early but not late Wnt5a blockade significantly reversed CPTP-induced activation of the non-canonical Wnt pathways, nerve regeneration, and inflammation. In contrast, a Wnt5a agonist decreased the pain threshold in both naive and painless rats. These results suggest that Wnt5a promotes the development of CPTP by activating non-canonical Wnt pathways, nerve regeneration, and inflammation. Therapeutic intervention by targeting Wnt5a may represent an effective strategy for preventing and treating CPTP.