Is AMPK a pharmacological target for the prevention of chronic pain?

Most drugs used to treat pain are utilized because they alleviate ongoing pain or hypersensitivity produced by injury.  One very common reason people take drugs to alleviate pain is to block the pain produced by a surgical procedure. While analgesics, including opioids, have completely changed the medical management of post-surgical pain over the last century, it is also clear that these post-surgical analgesics are not capable of preventing the development of chronic pain in at least a subset of people who have surgery. Why does this occur and how can we prevent this from happening?

The past decade or more of work on nociceptor signaling and physiology has demonstrated that these are remarkably plastic cells. This plasticity seems to be critical for the development of chronic pain after peripheral injury, such as surgery, and this plasticity may occur even in the presence of strong analgesics that act primarily on the central nervous system.  We and others have shown that a key signaling event for nociceptor plasticity is activation of signal transduction that leads to changes in gene expression at the level of translation. Key pathways involved in these events are the mechanistic target of rapamycin (mTOR) and mitogen activated protein kinase (MAPK) pathways.  Because these are redundant pathways in terms of translation control that converge on the same endpoints, targeting these pathways individually is unlikely to be sufficient to block nociceptor plasticity. Somewhat conveniently, cells have a natural signaling pathway that can negatively regulate mTOR and MAPK and this signaling molecule, called the AMP-activated protein kinase (AMPK), can be targeted with pharmacological activators.  We have shown, in a variety of models, that activating AMPK effectively alleviates mechanical hypersensitivity produced by injury.  Importantly, activating AMPK also prevents the development of chronic post-surgical pain in hyperalgesic priming models that effectively model long-term nociceptor plasticity. We have recently reviewed this evidence in a review article for a special issue of Neuroscience Letters on Pain Pharmacology here.

We speculate, based on the work we have conducted to this point, that AMPK activators may represent some of the first therapeutics that can be utilized to specifically prevent the development of chronic post-surgical pain. The best-known AMPK activator, metformin, happens to be one of the most widely prescribed and safest drugs in the world.  It also costs little more than pennies.  Much work is still needed to understand how the drug should be dosed for prevention of post-surgical pain and to determine if the standard prescription amount is sufficient to stimulate this pathway in human peripheral nervous system neurons following injury.  Having said that, the established safety and low cost of metformin make this, in our view, an exciting area for further development as a preventative therapeutic for chronic post-surgical pain and potentially other chronic pain disorders.

About Ted Price

Ted PriceTed Price did his Ph.D. at University of Texas Health Science Center in San Antonio working with Chris Flores, Ken Hargreaves and Armen Akopian. He then went onto postdoctoral work at McGill University with Fernando Cervero. He has been at University of Arizona for 6 years and is now an Associate Professor of Pharmacology.  His NIH funded lab works on molecular mechanisms driving the development of chronic pain.

About Greg Dussor

Dussor_Gregory_200802588_28Dr. Greg Dussor is an Associate Professor of Pharmacology at The University of Arizona in Tucson, AZ, USA.  Aside from working on AMPK activators in post-surgical pain models, the primary focus of his laboratory is headache disorders such as migraine.  His research team is studying the activation and plasticity of the trigeminal system that projects from the cranial meninges to better understand how this pathway may contribute to headache.

Reference

Price TJ, & Dussor G (2013). AMPK: An emerging target for modification of injury-induced pain plasticity. Neuroscience letters PMID: 23831352

Comments

  1. stuart miller says:

    Hi, fascinating research. Dr. Dussor, in working with post concussion patients, some have highlighted that big flucuations in blood sugar really aggravate their headaches – I noticed that metformin as an AMPK activator is proposed as an option for treatment for preventing and treating chronic pain. Has this been explored with patients with PCS ? What would be the difference in managing your glucose levels and taking metformin in terms of activating AMPK ? Could you speak to your work on headache management ? Sorry for my ignorance.