AMPK activation attenuates inflammatory pain through inhibiting NF-κB activation and IL-1β expression

J Neuroinflammation. 2019 Feb 12;16(1):34. doi: 10.1186/s12974-019-1411-x.


Background: Chronic pain is a major clinical problem with limited treatment options. Previous studies have demonstrated that activation of adenosine monophosphate-activated protein kinase (AMPK) can attenuate neuropathic pain. Inflammation/immune response at the site of complete Freund's adjuvant (CFA) injection is known to be a critical trigger of the pathological changes that produce inflammatory pain. However, whether activation of AMPK produces an analgesic effect through inhibiting the proinflammatory cytokines, including interleukin-1β (IL-1β), in inflammatory pain remains unknown.

Methods: Inflammatory pain was induced in mice injected with CFA. The effects of AICAR (5-aminoimidazole-4-carboxyamide ribonucleoside, an AMPK activator), Compound C (an AMPK inhibitor), and IL-1ra (an IL-1 receptor antagonist) were tested at day 4 after CFA injection. Inflammatory pain was assessed with von Frey filaments and hot plate. Immunoblotting, hematoxylin and eosin (H&E) staining, and immunofluorescence were used to assess inflammation-induced biochemical changes.

Results: The AMPK activator AICAR produced an analgesic effect and inhibited the level of proinflammatory cytokine IL-1β in the inflamed skin in mice. Moreover, activation of AMPK suppressed CFA-induced NF-κB p65 translocation from the cytosol to the nucleus in activated macrophages (CD68+ and CX3CR1+) of inflamed skin tissues. Subcutaneous injection of IL-1ra attenuated CFA-induced inflammatory pain. The AMPK inhibitor Compound C and AMPKα shRNA reversed the analgesic effect of AICAR and the effects of AICAR on IL-1β and NF-κB activation in inflamed skin tissues.

Conclusions: Our study provides new information that AMPK activation produces the analgesic effect by inhibiting NF-κB activation and reducing the expression of IL-1β in inflammatory pain.

Keywords: AMPK; IL-1β; Inflammatory pain; NF-κB.

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Aminoimidazole Carboxamide / analogs & derivatives*
  • Aminoimidazole Carboxamide / therapeutic use
  • Animals
  • Anti-Inflammatory Agents / therapeutic use
  • Antigens, CD / metabolism
  • Antigens, Differentiation, Myelomonocytic / metabolism
  • CX3C Chemokine Receptor 1 / genetics
  • CX3C Chemokine Receptor 1 / metabolism
  • Disease Models, Animal
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Freund's Adjuvant / toxicity
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Hypoglycemic Agents / therapeutic use*
  • Inflammation / chemically induced
  • Inflammation / complications
  • Inflammation / drug therapy
  • Interleukin 1 Receptor Antagonist Protein / therapeutic use
  • Interleukin-1beta / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • NF-kappa B / metabolism*
  • Pain / drug therapy
  • Pain / etiology
  • Pain / metabolism*
  • Pain Threshold / drug effects
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Ribonucleotides / therapeutic use*
  • Skin / drug effects
  • Skin / metabolism
  • Skin / pathology


  • Anti-Inflammatory Agents
  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • CD68 antigen, human
  • CX3C Chemokine Receptor 1
  • Cx3cr1 protein, mouse
  • Hypoglycemic Agents
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1beta
  • NF-kappa B
  • RNA, Small Interfering
  • Ribonucleotides
  • Aminoimidazole Carboxamide
  • Freund's Adjuvant
  • AMP-Activated Protein Kinases
  • AICA ribonucleotide