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

BackgroundChronic 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-1 (IL-1), in inflammatory pain remains unknown.MethodsInflammatory 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.ResultsThe AMPK activator AICAR produced an analgesic effect and inhibited the level of proinflammatory cytokine IL-1 in the inflamed skin in mice. Moreover, activation of AMPK suppressed CFA-induced NF-B 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 AMPK shRNA reversed the analgesic effect of AICAR and the effects of AICAR on IL-1 and NF-B activation in inflamed skin tissues.ConclusionsOur study provides new information that AMPK activation produces the analgesic effect by inhibiting NF-B activation and reducing the expression of IL-1 in inflammatory pain.