Bone cancer pain (BCP), due to cancer bone metastasis and bone destruction, is a common symptom of tumors, including breast, prostate, and lung tumors. Patients often experience severe pain without effective treatment. Here, using a mouse model of bone cancer, we report that MOTS-c, a novel mitochondrial-derived peptide, confers remarkable protection against cancer pain and bone destruction. Briefly, we find that the plasma level of endogenous MOTS-c is significantly lower in the BCP group than in the sham group. Accordingly, intraperitoneal administration of MOTS-c robustly attenuates bone cancer-induced pain. These effects are blocked by compound C, an AMPK inhibitor. Furthermore, MOTS-c treatment significantly enhances AMPKα_1/2 phosphorylation. Interestingly, mechanical studies indicate that at the spinal cord level, MOTS-c relieves pain by restoring mitochondrial biogenesis, suppressing microglial activation, and decreasing the production of inflammatory factors, which directly contribute to neuronal modulation. However, in the periphery, MOTS-c protects against local bone destruction by modulating osteoclast and immune cell function in the tumor microenvironment, providing long-term relief from cancer pain. Additionally, we find that chronic administration of MOTS-c has little effect on liver, renal, lipid or cardiac function in mice. In conclusion, MOTS-c improves BCP through peripheral and central synergistic effects on nociceptors, immune cells, and osteoclasts, providing a pharmacological and biological rationale for the development of mitochondrial peptide-based therapeutic agents for cancer-induced pain.

Painful Diabetic Neuropathy (PDN) is a common diabetes complication that frequently causes severe hyperalgesia and allodynia and presents treatment challenges. Mitochondrial-derived peptide (MOTS-c), a novel mitochondrial-derived peptide, has been shown to regulate glucose metabolism, insulin sensitivity, and inflammatory responses. This study aimed to evaluate the effects of MOTS-c in streptozocin (STZ)-induced PDN model and investigate the putative underlying mechanisms. We found that endogenous MOTS-c levels in plasma and spinal dorsal horn were significantly lower in STZ-treated mice than in control animals. Accordingly, MOTS-c treatment significantly improves STZ-induced weight loss, elevation of blood glucose, mechanical allodynia, and thermal hyperalgesia; however, these effects were blocked by dorsomorphin, an adenosine monophosphate-activated protein kinase (AMPK) inhibitor. In addition, MOTS-c treatment significantly enhanced AMPKα_1/2 phosphorylation and PGC-1α expression in the lumbar spinal cord of PDN mice. Mechanistic studies indicated that MOTS-c significantly restored mitochondrial biogenesis, inhibited microglia activation, and decreased the production of pro-inflammatory factors, which contributed to the alleviation of pain. Moreover, MOTS-c decreased STZ-induced pain hypersensitivity in PDN mice by activating AMPK/PGC-1α signaling pathway. This provides the pharmacological and biological evidence for developing mitochondrial peptide-based therapeutic agents for PDN.

Background: Arctigenin (AG), a natural lignan compound, has been reported to reveal its anti-inflammatory effects in glucose, lipid metabolism and type 2 diabetes mellitus. An increasing number of studies suggest that microglia activation evoked neuroinflammation is known to contribute to the development and progression of neuropathic pain. This study aims to investigate the role and mechanism of AG in ameliorating spared nerve injury (SNI)-induced neuropathic pain. Materials and methods: SNI model was defined as suffering severe hyperalgesia and allodynia and established in C57BL/6 male mice. The effects of AG on SNI mice and its underlying mechanisms were examined by behavioral tests, qPCR, western blotting, ELISA, immunofluorescence (IF), ROS test, transmission electron microscopy and mitochondrial test. Results: We found that intraperitoneal administration of AG produced pronounced dose-dependent antinociceptive effects in SNI mice. Moreover, AG treatment significantly inhibited ERK, JNK and p38 phosphorylation in the lumbar spinal cord of SNI mice, but not AMPK, PGC-α and mTOR pathway. Meanwhile, we found that pretreatment with the U0126 or SB203580 or SP600125, 30 min prior to AG administration, blocked the analgesic effects of AG in SNI mice. Furthermore, mechanistic studies indicated that at the spinal cord level, AG produced pain relief through restoring mitochondrial biogenesis, inhibiting oxidative damage, suppressing microglia and astrocyte activation and decreasing the production of pro-inflammatory factors, which direct contributed to neuronal modulation. pretreating with minocycline reduced but did not completely block the analgesic effect of AG, indicating that the activation of spinal cord microglia is not necessary for the antiallodynic effect of AG. In addition to neuropathic pain, AG exhibits significant analgesic effects across diverse models, indicating its broad-spectrum analgesic properties. Concurrently, studies on short-term toxic side effects revealed that prolonged AG injection had no impact on hepatic or renal functions and produced none of the typical analgesic side effects, including tolerance, addiction, or constipation, indicating limited antinociceptive side effect. Conclusions: The present study is the first to provide evidences that AG may represent a novel therapeutic target with high analgesic activity and low side effects for the treatment of neuropathic pain.