Metformin Attenuates Bone Cancer Pain by Reducing TRPV1 and ASIC3 Expression

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.

TRPV1 in dorsal root ganglion contributed to bone cancer pain

“…TRPV1 is broadly expressed in peripheral nervous system and the abnormal activity of TRPV1 is involved in a variety of pathophysiological processes, such as pain and itch. In DRG neurons, TRPV1 is predominantly located in small and medium neurons ( 10 – 12 ), the distribution of TRPV1 is consistent with the heat sensitivity of TRPV1. The bone cancer pain model led to an overall shift in the distribution of TRPV1 from small to large neurons, validating that large DRG neurons expressed TRPV1 ( 10 , 11 ).…”

“…In DRG neurons, TRPV1 is predominantly located in small and medium neurons ( 10 – 12 ), the distribution of TRPV1 is consistent with the heat sensitivity of TRPV1. The bone cancer pain model led to an overall shift in the distribution of TRPV1 from small to large neurons, validating that large DRG neurons expressed TRPV1 ( 10 , 11 ). In the bone cancer pain model, the TRPV1 channel contributes to the sensitization of DRG neurons ( 13 , 14 ).…”

Curcumin and metformin synergistically modulate peripheral and central immune mechanisms of pain

“…Curcumin was found to regulate TRPV1 channels in vivo via antagonizing their activation and inhibiting phosphorylation 25 , 54 . In addition, metformin was also found to modulate TRPV1 channels in a murine model of bone cancer via decreased ASIC3 and TRPV1 expression 55 . Therefore, inhibition of TRP receptors may also have a major contribution to the curcumin-metformin synergistic antinociception, which needs to be confirmed in future studies.…”

TET1-TRPV4 Signaling Contributes to Bone Cancer Pain in Rats

“…An ascending series of calibrated VFFs (0.6, 1.0, 1.4, 2.0, 4.0, 6.0, 8.0, 10.0, 15.0, and 26.0 g) was used to stimulate the plantar surface of the left hind paw, and each VFF was held for about 1–2 s. When the rat responded by lifting or adding its foot, it was considered positive; otherwise, it was considered negative. First, a von Frey filament stimulus weighing 0.6 g was selected and administered using the “up and down” method until a rat responded positively [ 29 ]. Following that, corresponding values were recorded with a cutoff value of 26.0 g, with at least 5 min between trials, and an average of 6 consecutive measurements.…”