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Published on: May 26, 2017
Antihyperalgesia effect of AMP-activated protein kinase (AMPK) activators in a mouse model of postoperative pain
Vaskar Das1, Jeffrey S Kroin1, Mario Moric1
1Department of Anesthesiology, Rush University Medical Center, Chicago, Illinois, USA.
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.
Insights
AMP-activated protein kinase (AMPK) activators, metformin and O304, reduce postoperative pain hypersensitivity in mice. These drugs also normalize the AMPK pathway in dorsal root ganglion neurons.
Area of Science:
- Neuroscience
- Pharmacology
- Pain Research
Background:
- AMP-activated protein kinase (AMPK) activators are known to decrease pain hypersensitivity.
- Postoperative pain models are crucial for understanding and treating pain after surgery.
Purpose of the Study:
- To investigate the efficacy of metformin and a novel AMPK activator, O304, in reducing mechanical hypersensitivity after surgery.
- To determine the effects of these AMPK activators on the AMPK pathway in dorsal root ganglion (DRG) neurons.
Main Methods:
- Postoperative pain was induced in mice via plantar hindpaw incision.
- Mice received oral gavage of vehicle, metformin (200 mg/kg), O304 (200 mg/kg), or a combination of O304 and metformin for 3 days post-surgery.
- Mechanical hypersensitivity was assessed using von Frey filaments, and DRG neurons were analyzed for changes in key proteins of the AMPK pathway via immunohistochemistry.
Main Results:
- Both O304 and metformin significantly reduced mechanical hypersensitivity in mice with postoperative pain compared to the vehicle group.
- The combination of O304 and metformin demonstrated an even greater increase in mechanical thresholds.
- Treatment with AMPK activators reversed the downregulation of the AMPK alpha subunit and the upregulation of mTOR and eIF2α observed in vehicle-treated mice.
Conclusions:
- Early administration of O304 or metformin effectively reduces mechanical hypersensitivity in a mouse model of postoperative pain.
- These AMPK activators normalize the AMPK signaling pathway within the DRG, suggesting a therapeutic potential for pain management.
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