title: The inhibition of spinal synaptic plasticity mediated by activation of AMP-activated protein kinase signaling alleviates the acute pain induced by oxaliplatin.
abstract: Our recent findings demonstrated that oxaliplatin entering CNS may directly induce spinal central sensitization, and contribute to the rapid development of CNS-related side effects including acute pain during chemotherapy. However, the mechanism is largely unclear. In the current study, we found that the amplitude of C-fiber-evoked field potentials was significantly increased and the expression of phosphorylated mammalian AMP-activated protein kinase α (AMPKα) was markedly decreased following high frequency stimulation (HFS) or single intraperitoneal injection of oxaliplatin (4mg/kg). Spinal local application of AMPK agonist metformin (25μg) prevented the long term potentiation (LTP) induction and the activation of mTOR/p70S6K signal pathway, and significantly attenuated the acute thermal hyperalgesia and mechanical allodynia following single oxaliplatin treatment. Importantly, we found that incubation of low concentration oxaliplatin at dose of 6.6nM (the detected concentration in CSF following a single intraperitoneal injection of oxaliplatin) also significantly inhibited the AMPKα activation and increased the amplitude of sEPSCs, the number of action potential, and the expression of p-mTOR and p-p70S6K in spinal cord slices. Metformin (25μg) or rapamycin (2μg) inhibited the increased excitability of dorsal horn neurons and the decrease of p-AMPKα expression induced by low concentration oxaliplatin incubation. Furthermore, spinal application of AMPK inhibitor compound C (5μg) induced the spinal LTP, thermal hyperalgesia and mechanical allodynia, and rapamycin attenuated the spinal LTP, the thermal hyperalgesia and mechanical allodynia following oxaliplatin treatment (i.p.). Local application of metformin significantly decreased the mTOR and p70S6K activation induced by tetanus stimulation or oxaliplatin (i.p.). These results suggested that the decreased AMPKα activity via negatively regulating mTOR/p70S6K signal pathway enhanced the synaptic plasticity and contributed to acute pain induced by low concentration of oxaliplatin entering CNS.
authors.affiliation: Zhongshan School of Medicine, Guangdong Province Key Laboratory of Brain Function and Disease, Faculty of Forensic Medicine, Sun Yat-Sen University, Guangzhou 510080, China.
authors.forename: Yun-Zhi
authors.initials: YZ
authors.lastname: Ling
authors.affiliation: Department of General Internal Medicine, The First Affiliated Hospital of Sun Yat-sen University, Sun Yet-Sen University, Guangzhou 510080, China.
authors.forename: Zhen-Yu
authors.initials: ZY
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Cancer Center, Sun Yat-Sen University, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
authors.forename: Han-Dong
authors.initials: HD
authors.lastname: Ou-Yang
authors.affiliation: Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Rehabilitation Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Ma
authors.affiliation: Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Rehabilitation Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
authors.forename: Shao-Ling
authors.initials: SL
authors.lastname: Wu
authors.affiliation: Zhongshan School of Medicine, Guangdong Province Key Laboratory of Brain Function and Disease, Faculty of Forensic Medicine, Sun Yat-Sen University, Guangzhou 510080, China.
authors.forename: Jia-You
authors.initials: JY
authors.lastname: Wei
authors.affiliation: Zhongshan School of Medicine, Guangdong Province Key Laboratory of Brain Function and Disease, Faculty of Forensic Medicine, Sun Yat-Sen University, Guangzhou 510080, China.
authors.forename: Huan-Huan
authors.initials: HH
authors.lastname: Ding
authors.affiliation: Zhongshan School of Medicine, Guangdong Province Key Laboratory of Brain Function and Disease, Faculty of Forensic Medicine, Sun Yat-Sen University, Guangzhou 510080, China.
authors.forename: Xiao-Long
authors.initials: XL
authors.lastname: Zhang
authors.affiliation: Zhongshan School of Medicine, Guangdong Province Key Laboratory of Brain Function and Disease, Faculty of Forensic Medicine, Sun Yat-Sen University, Guangzhou 510080, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Liu
authors.affiliation: Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Rehabilitation Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China. Electronic address: lucyliucuicui@126.com.
authors.forename: Cui-Cui
authors.initials: CC
authors.lastname: Liu
authors.affiliation: Zhongshan School of Medicine, Guangdong Province Key Laboratory of Brain Function and Disease, Faculty of Forensic Medicine, Sun Yat-Sen University, Guangzhou 510080, China. Electronic address: Huangzhzh3@mail.sysu.edu.cn.
authors.forename: Zhen-Zhen
authors.initials: ZZ
authors.lastname: Huang
authors.affiliation: Zhongshan School of Medicine, Guangdong Province Key Laboratory of Brain Function and Disease, Faculty of Forensic Medicine, Sun Yat-Sen University, Guangzhou 510080, China.
authors.forename: Wen-Jun
authors.initials: WJ
authors.lastname: Xin
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D059787:Acute Pain / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005071:Evoked Potentials / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006930:Hyperalgesia / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects; D009473:Neuronal Plasticity / Q000187:drug effects*; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D013116:Spinal Cord / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D010751:Phosphopyruvate Hydratase
keywords: AMPKα; Acute pain; LTP; Oxaliplatin; mTOR/p70S6K signal pathway