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Antihyperalgesia effect of AMP-activated protein kinase (AMPK) activators in a mouse model of postoperative pain
  1. Vaskar Das,
  2. Jeffrey S Kroin,
  3. Mario Moric,
  4. Robert J McCarthy and
  5. Asokumar Buvanendran
  1. Department of Anesthesiology, Rush University Medical Center, Chicago, Illinois, USA
  1. Correspondence to Dr Asokumar Buvanendran, Department of Anesthesiology, Rush University Medical Center, Chicago, IL 60612, USA; Asokumar{at}


Background and objectives AMP-activated protein kinase (AMPK) activator drugs decrease hypersensitivity in mice with pain. This study examines if postsurgery treatment with the prototype AMPK activator metformin and a new mechanism-specific AMPK activator, O304, after plantar hindpaw incision in mice, would reduce mechanical hypersensitivity and produce changes in the AMPK pathway in the dorsal root ganglion (DRG).

Methods To create postoperative pain, an incision was made in the left plantar hindpaw. Animals were randomized into four oral gavage drug treatment groups (n=8/group): (1) vehicle, (2) metformin 200 mg/kg, (3) O304 200 mg/kg and (4) O304 200 mg/kg plus metformin 200 mg/kg. Drug gavages were performed 4 hours postsurgery and were repeated for 3 days. Mechanical hypersensitivity was measured with von Frey filaments. Changes in phosphorylated AMP-activated protein kinase alpha subunit, phosphorylated mechanistic target of rapamycin and phosphorylated eukaryotic initiation factor 2 alpha in DRG neurons were examined by immunohistochemistry.

Results O304 or metformin increased von Frey thresholds (reduced mechanical hypersensitivity) in plantar incision mice versus vehicle-treated incision mice between days 1 and 4 (difference of mean area under the curve, O304: 2.24 g*day; 95% CI of the difference 0.28 to 4.21, p=0.011; metformin: 2.56 g*day; 95% CI of the difference 1.71 to 3.41, p<0.001). The drug combination further elevated von Frey thresholds. In the vehicle-treated group, the AMP-activated protein kinase alpha subunit was downregulated and mechanistic target of rapamycin and eukaryotic initiation factor 2 alpha were upregulated in DRG neurons; these deficits were reversed by the AMPK activator treatments.

Conclusions Early treatment with the mechanism-specific AMPK activator O304 or the prototype AMPK activator metformin reduces mechanical hypersensitivity in a postoperative pain model in mice. These drugs also normalize the AMPK pathway in the DRG.

  • postoperative pain
  • pain medicine
  • animal studies
  • basic science of pain
  • pharmacology: other

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  • Contributors VD, JSK, MM and AB contributed to the experimental design. VD and JSK performed the experiments. VD collected the experimental data. VD performed the immunohistochemistry. MM and RJM contributed to the statistical analysis. VD, JSK, RJM and AB drafted the manuscript. VD, JSK, MM, RJM and AB reviewed and approved the final manuscript.

  • Funding University Anesthesiologists, S.C., Chicago, IL.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval The Institutional Animal Use and Care Committee of Rush University Medical Center, Chicago, IL, USA.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available upon reasonable request.