title: AMPK Phosphorylation Modulates Pain by Activation of NLRP3 Inflammasome.
abstract: OBJECTIVE
  Impairment in adenosine monophosphate-activated protein kinase (AMPK) activity and NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation are associated with several metabolic and inflammatory diseases. In this study, we investigated the role of AMPK/NLRP3 inflammasome axis in the molecular mechanism underlying pain perception.
  
  
  RESULTS
  Impairment in AMPK activation induced by compound C or sunitinib, two AMPK inhibitors, provoked hyperalgesia in mice (p<0.001) associated with marked NLRP3 inflammasome protein activation and increased serum levels of interleukin-1β (IL-1β) (24.56±0.82 pg/ml) and IL-18 (23.83±1.882 pg/ml) compared with vehicle groups (IL-1β: 8.15±0.44; IL-18: 4.92±0.4). This effect was rescued by increasing AMPK phosphorylation via metformin treatment (p<0.001), caloric restriction diet (p<0.001), or NLRP3 inflammasome genetic inactivation using NLRP3 knockout (nlrp3(-/-)) mice (p<0.001). Deficient AMPK activation and overactivation of NLRP3 inflammasome axis were also observed in blood cells from patients with fibromyalgia (FM), a prevalent human chronic pain disease. In addition, metformin treatment (200 mg/daily), which increased AMPK activation, restored all biochemical alterations examined by us in blood cells and significantly improved clinical symptoms, such as, pain, fatigue, depression, disturbed sleep, and tender points, in patients with FM.
  
  
  CONCLUSIONS
  These data suggest that AMPK/NLRP3 inflammasome axis participates in chronic pain and that NLRP3 inflammasome inhibition by AMPK modulation may be a novel therapeutic target to fight against chronic pain and inflammatory diseases as FM.
authors.affiliation: 1 Institute of Biomedicine of Seville (IBIS)/Research Laboratory, Oral Medicine Department, Universidad de Sevilla , Sevilla, Spain .
authors.forename: Pedro
authors.initials: P
authors.lastname: Bullón
authors.affiliation: 1 Institute of Biomedicine of Seville (IBIS)/Research Laboratory, Oral Medicine Department, Universidad de Sevilla , Sevilla, Spain .|2 Centro Andaluz de Biología del Desarrollo (CABD), Universidad Pablo de Olavide-CSIC-Junta de Andalucía and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) , ISCIII, Sevilla, Spain .
authors.forename: Elísabet
authors.initials: E
authors.lastname: Alcocer-Gómez
authors.affiliation: 3 División de Neurociencias, Universidad Pablo de Olavide de Sevilla , Sevilla, Spain .
authors.forename: Angel M
authors.initials: AM
authors.lastname: Carrión
authors.affiliation: 1 Institute of Biomedicine of Seville (IBIS)/Research Laboratory, Oral Medicine Department, Universidad de Sevilla , Sevilla, Spain .
authors.forename: Fabiola
authors.initials: F
authors.lastname: Marín-Aguilar
authors.affiliation: 2 Centro Andaluz de Biología del Desarrollo (CABD), Universidad Pablo de Olavide-CSIC-Junta de Andalucía and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) , ISCIII, Sevilla, Spain .
authors.forename: Juan
authors.initials: J
authors.lastname: Garrido-Maraver
authors.affiliation: 1 Institute of Biomedicine of Seville (IBIS)/Research Laboratory, Oral Medicine Department, Universidad de Sevilla , Sevilla, Spain .
authors.forename: Lourdes
authors.initials: L
authors.lastname: Román-Malo
authors.affiliation: 4 CIBER de Enfermedades Respiratorias, Madrid, Spain; Advanced Imaging Unit, Centro Nacional de Investigaciones Cardiovasculares, and Universidad Complutense Madrid , Madrid, Spain .
authors.forename: Jesus
authors.initials: J
authors.lastname: Ruiz-Cabello
authors.affiliation: 5 Faculty of Pharmacy and Biochemistry, University of Zagreb , Zagreb, Croatia .
authors.forename: Ognjen
authors.initials: O
authors.lastname: Culic
authors.affiliation: 6 University and CNRS , UMR7355, Orléans, France .
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
authors.affiliation: 7 INSERM , UMR866, Dijon, France .|8 Centre Georges François Leclerc , Dijon, France .|9 Université de Bourgogne , Dijon, France .
authors.forename: Lionel
authors.initials: L
authors.lastname: Apetoh
authors.affiliation: 7 INSERM , UMR866, Dijon, France .|8 Centre Georges François Leclerc , Dijon, France .|9 Université de Bourgogne , Dijon, France .
authors.forename: François
authors.initials: F
authors.lastname: Ghiringhelli
authors.affiliation: 10 Dipartimento di Scienze Cliniche Specialistiche ed Odontostomatologiche-Sez. Biochimica, Università Politecnica delle Marche , Ancona, Italy .
authors.forename: Maurizio
authors.initials: M
authors.lastname: Battino
authors.affiliation: 2 Centro Andaluz de Biología del Desarrollo (CABD), Universidad Pablo de Olavide-CSIC-Junta de Andalucía and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) , ISCIII, Sevilla, Spain .
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Sánchez-Alcazar
authors.affiliation: 1 Institute of Biomedicine of Seville (IBIS)/Research Laboratory, Oral Medicine Department, Universidad de Sevilla , Sevilla, Spain .
authors.forename: Mario D
authors.initials: MD
authors.lastname: Cordero
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D000328:Adult; D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D005356:Fibromyalgia / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism*; D020382:Interleukin-18 / Q000097:blood; D053583:Interleukin-1beta / Q000097:blood; D008297:Male; D008687:Metformin / Q000008:administration & dosage; D051379:Mice; D008875:Middle Aged; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010146:Pain / Q000235:genetics* / Q000473:pathology; D058748:Pain Perception / Q000187:drug effects; D010766:Phosphorylation; D011758:Pyrroles / Q000008:administration & dosage; D000077210:Sunitinib
chemical_list: D002352:Carrier Proteins; D007211:Indoles; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D011758:Pyrroles; D008687:Metformin; D055372:AMP-Activated Protein Kinases; D000077210:Sunitinib