Tetrahydropalmatine has analgesic role in mouse model of bone cancer pain by inactivating the TNF-α/uPA/PAR2/TRPV1 pathway in dorsal root ganglia

Background: Treatment of bone Cancer pain (BCP) remains a challenge. The current paper was to research the analgesic effect of Tetrahydropalmatine (THP) on BCP and the related mechanisms.

Methods: Mouse model of BCP was constructed by injecting E0771 breast Cancer cells into the tibia. Behavioral test was performed to research the effect of THP on pain nociception of BCP mice. Tibia and dorsal root ganglia (DRG) damage was evaluated by HE and Nissl staining. The construction of BCP cell models was conducted by co-culture DRG neurons with E0771 breast Cancer cells. The effect of THP on the viability and Apoptosis of BCP cell models was monitored by CCK-8 and Tunel assays. TNF-α/uPA/PAR2/TRPV1 pathway activity in DRG was detected by qRT-PCR and Western blot. Pomalidomide (PMA), exogenous TNF-α protein and Capsaicin were utilized to treat BCP mouse model and cell models to explore whether THP exerted analgesic effect via inactivating the TNF-α/uPA/PAR2/TRPV1 pathway.

Results: THP attenuated pain nociception, relieved tibia destruction, and mitigated inflammation, neuronal death and neuronal excitotoxicity in DRG of BCP mice. It enhanced the viability, but suppressed the Apoptosis of BCP cell models. The activated TNF-α/uPA/PAR2/TRPV1 pathway in BCP mouse model and cell models was abrogated by THP treatment. PMA and THP had additive effect, which combination attenuated pain nociception, tibia and DRG damage of BCP mice, and Apoptosis of BCP cell models. The pain relief and the TNF-α/uPA/PAR2/TRPV1 pathway inactivation induced by THP in BCP mice was abolished by exogenous TNF-α protein or Capsaicin.

Conclusion: THP exerted the analgesic role in BCP might be through inactivating the TNF-α/uPA/PAR2/TRPV1 pathway in DRG. It may be an effective drug for relieving BCP in patients.

BCP; DRG damage; THP; TNF-α/uPA/PAR2/TRPV1; Tibia destruction.