Resveratrol suppresses bone cancer pain in rats by attenuating inflammatory responses through the AMPK/Drp1 signaling

Abstract

Bone cancer pain (BCP) is induced by primary bone cancer and secondary bone metastasis. During BCP pathogenesis, activated spinal astrocytes release proinflammatory cytokines, which participate in pain information transmission. In this study, we found that BCP rats showed disruption of trabecular bone structure, mechanical allodynia, and spinal inflammation. Moreover, reduced adenosine monophosphate-activated protein kinase (AMPK) activity, increased mitochondrial fission-associated protein Drp1 GTPase activity accompanied by the dysfunction of mitochondrial function, and abnormal BAX and Bcl-2 expression were found in the spinal cord of BCP rats. Notably, these alterations are reversed by resveratrol (Res) administration. Cell experiment results demonstrated that Res promotes mitochondrial function by activating AMPK, decreasing Drp1 activity, and inhibiting tumor necrosis factor-α-induced mitochondrial membrane potential reduction. Taken together, these results indicate that Res suppresses BCP in rats by attenuation of the inflammatory responses through the AMPK/Drp1 signaling pathway.

Targeted up-regulation of Drp1 in dorsal horn attenuates neuropathic pain hypersensitivity by increasing mitochondrial fission

“…Our previous study has shown that Drp1 is highly expressed at the spinal cord level [ 33 ]. And many studies have shown different NP contributed to the increased expression of Drp1 [ [34] , [35] , [36] , [37] , [38] , [39] , [40] , [41] , [42] ]. Here we observed the changes of Drp1 in the SDH of the mice during NP by Western blot and qRT-PCR and also confirmed the increased Drp1 expression ( Fig.…”

“…Li MY et al also have observed the increased Drp1, but decreased phosphorylated-Drp1, at spinal cord by Western blot in bone cancer -induced NP model [ 38 ]. Similarly, Hao MM et al have reported decreased phosphorylated-Drp1 at spinal cord by Western blot in bone cancer -induced NP model [ 37 ]. At the same time, Zhan L et al have shown the increased Mfn1 and Opa1 proteins at DRG by Western blot CCI model [ 40 ].…”

“…Due to its complexity of pathogenesis and adverse reactions to drugs, its therapeutic treatment remains a challenge. Among all mechanistic studies, accumulating evidence has pointed to mitochondrial dysfunction [ [34] , [35] , [36] , [37] , [38] , [39] , [40] , [41] , [42] , 45 ]. Neurons are dependent on mitochondria, which not only provide energy to power cellular function through oxidative phosphorylation, but also regulate cellular oxidation-reduction status, calcium levels, signal transduction, and apoptosis [ 58 ].…”

Phosphoproteomic Profiling of Rat’s Dorsal Root Ganglia Reveals mTOR as a Potential Target in Bone Cancer Pain and Electro-Acupuncture’s Analgesia

“…It is reported that MAPK and PI3K signaling pathways were involved in the upregulation of DRG TRPV1 expression under endogenous formaldehyde stimulation, thus playing an important role in BCP ( Han et al, 2012 ). Activation of AMPK signaling pathway mediated spinal neuroinflammation or inflammatory responses for the attenuation of BCP ( Han et al, 2012 ; Hao et al, 2020 ). In addition, many studies have already shown that MAPK and PI3K/Akt signaling pathways were involved in BCP mechanism from either the spinal cord or DRG level ( Fang et al, 2015 ; Guan et al, 2015 ; Ni et al, 2019 ; Zhao et al, 2019 ).…”

Electroacupuncture Attenuates Inflammatory Pain by Activating AMPK/autophagy and Inhibiting iNOS and IL-1β in Inflamed Tissues

“…Many studies have shown that AMPK activation reduces in ammatory pain [25,26]. Further research found that EA also plays analgesic effects on in ammatory pain partially via activating the AMPK pathway in the spinal cord [8].…”