Numerous studies have shown that mitochondrial dysfunction manifested by increased mitochondrial permeability transition pore (mPTP) opening and reactive oxygen species (ROS) level, and decreased mitochondrial membrane potential (MMP) plays an important role in the development of neuropathic pain. Sirtuin3 (SIRT3), a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase, has been shown to inhibit mitochondrial oxidative stress. However, the role of SIRT3 in neuropathic pain is unclear. In this study, we found that the protein and mRNA levels of SIRT3 were significantly downregulated in the spinal cords of spared nerve injury- (SNI-) induced neuropathic pain mice, while overexpression of spinal SIRT3 reversed SNI-induced pain hypersensitivity. Further study showed that SIRT3 overexpression reduced the acetylation level of lysine 166 (K166) on cyclophilin D (CypD), the regulatory component of the mPTP, inhibited the mPTP opening, decreased ROS and malondialdehyde (MDA) levels, and increased MMP and manganese superoxide dismutase (MnSOD) in SNI mice. Point mutation of K166 to arginine on CypD (CypD-K166R) abrogated SNI-induced mitochondrial dysfunction and neuropathic pain in mice. Moreover, inhibiting mPTP opening by cyclosporin A (CsA) improved mitochondrial function and neuropathic pain in SNI mice. Together, these data show that SIRT3 is necessary to prevent neuropathic pain by deacetylating CypD-K166 and further improving mitochondrial dysfunction. This study may shed light on a potential drug target for the treatment of neuropathic pain.
Long-term chronic pain can lead to depression. However, the mechanism underlying chronic pain-related depression remains unclear. Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase (HDAC). Our previous studies have demonstrated that SIRT1 in the central nucleus of the amygdala (CeA) is involved in the development of chronic pain-related depression. In addition, increasing studies have indicated that long non-coding RNAs (lncRNAs) play a vital role in the pathogenesis of pain or depression. However, whether lncRNAs are involved in SIRT1-mediated chronic pain-related depression remains largely unknown. In this study, we identified that a novel lncRNA-84277 in CeA was the upstream molecule to regulate SIRT1 expression. Functionally, lncRNA-84277 overexpression in CeA significantly alleviated the depression-like behaviors in spared nerve injury (SNI)-induced chronic pain rats, whereas lncRNA-84277 knockdown in CeA induced the depression-like behaviors in naïve rats. Mechanically, lncRNA-84277 acted as a competing endogenous RNA (ceRNA) to upregulate SIRT1 expression by competitively sponging miR-128-3p, and therefore improved chronic pain-related depression-like behaviors. Our findings reveal the critical role of lncRNA-84277 in CeA specifically in guarding against chronic pain-related depression via a ceRNA mechanism and provide a potential therapeutic target for chronic pain-related depression.
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