Format

Send to

Choose Destination
Antioxid Redox Signal. 2016 Jan 20;24(3):157-70. doi: 10.1089/ars.2014.6120. Epub 2015 Sep 16.

AMPK Phosphorylation Modulates Pain by Activation of NLRP3 Inflammasome.

Author information

1
1 Institute of Biomedicine of Seville (IBIS)/Research Laboratory, Oral Medicine Department, Universidad de Sevilla , Sevilla, Spain .
2
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 .
3
3 División de Neurociencias, Universidad Pablo de Olavide de Sevilla , Sevilla, Spain .
4
4 CIBER de Enfermedades Respiratorias, Madrid, Spain; Advanced Imaging Unit, Centro Nacional de Investigaciones Cardiovasculares, and Universidad Complutense Madrid , Madrid, Spain .
5
5 Faculty of Pharmacy and Biochemistry, University of Zagreb , Zagreb, Croatia .
6
6 University and CNRS , UMR7355, Orléans, France .
7
7 INSERM , UMR866, Dijon, France .
8
8 Centre Georges François Leclerc , Dijon, France .
9
9 Université de Bourgogne , Dijon, France .
10
10 Dipartimento di Scienze Cliniche Specialistiche ed Odontostomatologiche-Sez. Biochimica, Università Politecnica delle Marche , Ancona, Italy .

Abstract

AIMS:

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.

INNOVATION AND 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.

PMID:
26132721
PMCID:
PMC4742979
DOI:
10.1089/ars.2014.6120
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Atypon Icon for PubMed Central
Loading ...
Support Center