Alleviation of paclitaxel-induced mechanical hypersensitivity and hyperalgesic priming with AMPK activators in male and female mice.

AMP-activated protein kinase (AMPK) is an energy-sensing kinase that has emerged as a novel therapeutic target for pain due to its ability to inhibit mechanistic target of rapamycin (mTOR) and mitogen activated protein kinase (MAPK) signaling, two signaling pathways that are linked to pain promotion after injury as well as the development of hyperalgesic priming. MAPK and mTOR signaling are also implicated in chemotherapy induced peripheral neuropathy (CIPN). We conducted a series of experiments to gain further insight into how AMPK activators might best be used to treat pain in both sexes in the setting of CIPN from paclitaxel.

Indirect AMP-Activated Protein Kinase Activators Prevent Incision-Induced Hyperalgesia and Block Hyperalgesic Priming, Whereas Positive Allosteric Modulators Block Only Priming in Mice.

AMP-activated protein kinase (AMPK) is a multifunctional kinase that negatively regulates the mechanistic target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) signaling, two signaling pathways linked to pain promotion after injury, such as surgical incision. AMPK can be activated directly using positive allosteric modulators, as well as indirectly through the upregulation of upstream kinases, such as liver kinase B1 (LKB1), which is a mechanism of action of metformin. Metformin's antihyperalgesic effects occur only in male mice, raising questions about how metformin regulates pain sensitivity.

The antidiabetic drug metformin prevents and reverses neuropathic pain and spinal cord microglial activation in male but not female mice.

Metformin is a widely prescribed drug used in the treatment of type II diabetes. While the drug has many mechanisms of action, most of these converge on AMP activated protein kinase (AMPK), which metformin activates. AMPK is a multifunctional kinase that is a negative regulator of mechanistic target of rapamycin (mTOR) and mitogen activated protein kinase (MAPK) signaling.