Metformin Attenuates Bone Cancer Pain by Reducing TRPV1 and ASIC3 Expression

He-Ya Qian; Fang Zhou; Rui Wu; Xiao-Jun Cao; Tao Zhu; Hao-Dong Yuan; Ya-Nan Chen; Ping-An Zhang

doi:10.3389/fphar.2021.713944

Metformin Attenuates Bone Cancer Pain by Reducing TRPV1 and ASIC3 Expression

Front Pharmacol. 2021 Aug 4:12:713944. doi: 10.3389/fphar.2021.713944. eCollection 2021.

Authors

He-Ya Qian^{1

2}, Fang Zhou¹, Rui Wu², Xiao-Jun Cao², Tao Zhu³, Hao-Dong Yuan³, Ya-Nan Chen¹, Ping-An Zhang^{2

4}

Affiliations

¹ Department of Oncology, Affiliated Zhangjiagang Hospital of Soochow University, Zhangjiagang, China.
² Center for Translational Medicine, Affiliated Zhangjiagang Hospital of Soochow University, Zhangjiagang, China.
³ Department of Laboratory, Affiliated Zhangjiagang Hospital of Soochow University, Zhangjiagang, China.
⁴ Center for Translational Pain Medicine, Institute of Neuroscience, Soochow University, Suzhou, China.

Abstract

Bone cancer pain (BCP) is a common pathologic pain associated with destruction of bone and pathological reconstruction of nervous system. Current treatment strategies in clinical is inadequate and have unacceptable side effects due to the unclear pathology mechanism. In the present study, we showed that transplantation of Walker 256 cells aggravated mechanical allodynia of BCP rats (**p < 0.01 vs. Sham), and the expression of ASIC3 (Acid-sensitive ion channel 3) and TRPV1 was obviously enhanced in L4-6 dorsal root ganglions (DRGs) of BCP rats (**p < 0.01 vs. Sham). ASIC3 and TRPV1 was mainly expressed in CGRP and IB4 positive neurons of L4-6 DRGs. While, TRPV1 but not ASIC3 was markedly upregulated in L4-6 spinal dorsal horn (SDH) of BCP rats (**p < 0.01 vs. Sham). Importantly, intrathecal injection of CPZ (a TRPV1 inhibitor) or Amiloride (an ASICs antagonist) markedly increased the paw withdraw threshold (PWT) of BCP rats response to Von Frey filaments (**p < 0.01 vs. BCP + NS). What's more, intraperitoneally injection of Metformin or Vinorelbine markedly elevated the PWT of BCP rats, but reduced the expression of TRPV1 and ASIC3 in L4-6 DRGs and decreased the TRPV1 expression in SDH (*p < 0.05, **p < 0.01 vs. BCP + NS). Collectively, these results suggest an effective analgesic effect of Metformin on mechanical allodynia of BCP rats, which may be mediated by the downregulation of ASIC3 and TRPV1.

Keywords: ASIC3; TRPV1; bone cancer pain; dorsal root ganglions; metformin.