title: Activation of Adenosine Monophosphate-activated Protein Kinase Suppresses Neuroinflammation and Ameliorates Bone Cancer Pain: Involvement of Inhibition on Mitogen-activated Protein Kinase.
abstract: BACKGROUND
  Activation of adenosine monophosphate-activated kinase (AMPK) has been associated with the inhibition of inflammatory nociception and the attenuation of morphine antinociceptive tolerance. In this study, the authors investigated the impact of AMPK activation through resveratrol treatment on bone cancer pain.
  
  
  METHODS
  The nociception was assessed by measuring the incidence of foot withdrawal in response to mechanical indentation in rats (n = 8). Cytokine expression was measured using quantitative polymerase chain reaction (n = 8). Cell signalings were assayed by western blot (n = 4) and immunohistochemistry (n = 5). The microglial cell line BV-2, primary astrocytes, and neuron-like SH-SY5Y cells were cultured to investigate the in vitro effects.
  
  
  RESULTS
  Resveratrol and 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide, the AMPK activators, significantly attenuated bone cancer pain in rats with tumor cell implantation (TCI; threshold of mechanical withdrawal, resveratrol vs. vehicle: 10.1 ± 0.56 vs. 4.1 ± 0.37; 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide vs. vehicle: 8.2 ± 0.17 vs. 4.1 ± 0.37, mean ± SEM); these effects were reversed by the AMPK inhibitor compound C (compound C vs. resveratrol: 6.2 ± 1.35 vs. 10.1 ± 0.56, mean ± SEM). Resveratrol has an AMPK-dependent inhibitory effect on TCI-evoked astrocyte and microglial activation. The antinociceptive effects of resveratrol were partially mediated by the reduced phosphorylation of mitogen-activated protein kinases and decreased production of proinflammatory cytokines in an AMPK-dependent manner. Furthermore, resveratrol potently inhibited inflammatory factors-mediated protein kinase B/mammalian target of rapamycin signaling in neurons. Acute pain evoked by proinflammatory cytokines in the spinal cord was significantly attenuated by resveratrol.
  
  
  CONCLUSIONS
  AMPK activation in the spinal glia by resveratrol may have utility in the treatment of TCI-induced neuroinflammation, and our results further implicate AMPK as a novel target for the attenuation of bone cancer pain.
authors.affiliation: From the Department of Pharmacology, Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Jiangsu, China (H.S., Y.H., C.P., X.D., W.D., L.H., C.J., Y.Y., W.L.); State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Jiangsu, China (H.S., X.W.); Jiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical College, Xuzhou, Jiangsu, China (Y.H.); Department of Pain Management, Cancer Biotherapy Center, The Second Affiliated Hospital of Nanjing Medical University, Jiangsu, China (Z.C.); Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Jiangsu, China (F.L.); and Research Division of Pharmacology, China Pharmaceutical University, Nanjing, China (X.D., W.D., G.Z.).
authors.forename: Huayuan
authors.initials: H
authors.lastname: Song
authors.forename: Yuan
authors.initials: Y
authors.lastname: Han
authors.forename: Cailong
authors.initials: C
authors.lastname: Pan
authors.forename: Xueting
authors.initials: X
authors.lastname: Deng
authors.forename: Wenling
authors.initials: W
authors.lastname: Dai
authors.forename: Liang
authors.initials: L
authors.lastname: Hu
authors.forename: Chunyi
authors.initials: C
authors.lastname: Jiang
authors.forename: Yanjing
authors.initials: Y
authors.lastname: Yang
authors.forename: Zhixiang
authors.initials: Z
authors.lastname: Cheng
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.forename: Guangqin
authors.initials: G
authors.lastname: Zhang
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Wu
authors.forename: Wentao
authors.initials: W
authors.lastname: Liu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001859:Bone Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000517:prevention & control; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010146:Pain / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D047428:Protein Kinase Inhibitors; D013267:Stilbenes; D020928:Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; D000077185:Resveratrol