title: Procyanidins alleviates morphine tolerance by inhibiting activation of NLRP3 inflammasome in microglia.
abstract: BACKGROUND
  The development of antinociceptive tolerance following repetitive administration of opioid analgesics significantly hinders their clinical use. Evidence has accumulated indicating that microglia within the spinal cord plays a critical role in morphine tolerance. The inhibitor of microglia is effective to attenuate the tolerance; however, the mechanism is not fully understood. Our present study investigated the effects and possible mechanism of a natural product procyanidins in improving morphine tolerance via its specific inhibition on NOD-like receptor protein3 (NLRP3) inflammasome in microglia.
  
  
  METHODS
  CD-1 mice were used for tail-flick test to evaluate the degree of pain. The microglial cell line BV-2 was used to investigate the effects and the mechanism of procyanidins. Reactive oxygen species (ROS) produced from BV-2 cells was evaluated by flow cytometry. Cell signaling was measured by western blot assay and immunofluorescence assay.
  
  
  RESULTS
  Co-administration of procyanidins with morphine potentiated its antinociception effect and attenuated the development of acute and chronic morphine tolerance. Procyanidins also inhibited morphine-induced increase of interleukin-1β and activation of NOD-like receptor protein3 (NLRP3) inflammasome. Furthermore, procyanidins decreased the phosphorylation of p38 mitogen-activated protein kinase, inhibited the translocation of nuclear factor-κB (NF-κB), and suppressed the level of reactive oxygen species in microglia.
  
  
  CONCLUSIONS
  Procyanidins suppresses morphine-induced activation of NLRP3 inflammasome and inflammatory responses in microglia, and thus resulting in significant attenuation of morphine antinociceptive tolerance.
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Han-Zhong Road, Nanjing, 210029, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Han-Zhong Road, Nanjing, 210029, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Kong
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
authors.forename: Yin-Bing
authors.initials: YB
authors.lastname: Pan
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Han-Zhong Road, Nanjing, 210029, China.
authors.forename: Lai
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Han-Zhong Road, Nanjing, 210029, China.
authors.forename: Xiu-Xiu
authors.initials: XX
authors.lastname: Pan
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Han-Zhong Road, Nanjing, 210029, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Hu
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
authors.forename: Yan-Ning
authors.initials: YN
authors.lastname: Qian
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Han-Zhong Road, Nanjing, 210029, China. jcy@njmu.edu.cn.
authors.forename: Chun-Yi
authors.initials: CY
authors.lastname: Jiang
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Han-Zhong Road, Nanjing, 210029, China. painresearch@njmu.edu.cn.
authors.forename: Wen-Tao
authors.initials: WT
authors.lastname: Liu
mesh_terms: D065767:Activation, Metabolic / Q000187:drug effects; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004357:Drug Synergism; D004361:Drug Tolerance; D058847:Inflammasomes / Q000235:genetics*; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D009020:Morphine / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010147:Pain Measurement / Q000187:drug effects; D044945:Proanthocyanidins / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis
chemical_list: D000701:Analgesics, Opioid; C587672:IL1B protein, mouse; D058847:Inflammasomes; D053583:Interleukin-1beta; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D044945:Proanthocyanidins; D009020:Morphine; D048051:p38 Mitogen-Activated Protein Kinases