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Targeting AMPK for the Alleviation of Pathological Pain


Targeting AMPK for the Alleviation of Pathological Pain

Marina N Asiedu et al. Exp Suppl.


Chronic pain is a major clinical problem that is poorly treated with available therapeutics. Adenosine monophosphate-activated protein kinase (AMPK) has recently emerged as a novel target for the treatment of pain with the exciting potential for disease modification. AMPK activators inhibit signaling pathways that are known to promote changes in the function and phenotype of peripheral nociceptive neurons and promote chronic pain. AMPK activators also reduce the excitability of these cells suggesting that AMPK activators may be efficacious for the treatment of chronic pain disorders, like neuropathic pain, where changes in the excitability of nociceptors is thought to be an underlying cause. In agreement with this, AMPK activators have now been shown to alleviate pain in a broad variety of preclinical pain models indicating that this mechanism might be engaged for the treatment of many types of pain in the clinic. A key feature of the effect of AMPK activators in these models is that they can lead to a long-lasting reversal of pain hypersensitivity even long after treatment cessation, indicative of disease modification. Here, we review the evidence supporting AMPK as a novel pain target pointing out opportunities for further discovery that are likely to have an impact on drug discovery efforts centered around potent and specific allosteric activators of AMPK for chronic pain treatment.

Keywords: AMPK; Cancer pain;; MAPK; Neuropathic pain; Postsurgical pain; mTOR.

Conflict of interest statement

The authors declare no conflicts of interest.


Fig. 11.1
Fig. 11.1
Impact of AMPK activation on pathological pain-related signaling cascades. Factors associated with pathological pain employ signaling mechanisms that converge onto the mTORC1 and MAPK pathways to induce and maintain pain plasticity in nociceptors. Activation of AMPK abrogates these effects by negatively regulating these signaling events via phosphorylation of key effector molecules. AMPK activation phosphorylates IRS, an adaptor protein of the Trk receptor, at Ser789 to inhibit signaling via Trk and Insulin/IGF1 receptors. AMPK activation dampens mTORC1 signaling by phosphorylating TSC1/2 at Ser 1227 and 1345. The phosphorylation of Braf (Raf), a small GTPase linking receptors to MAPK signaling, by AMPK attenuates downstream ERK signaling. These signaling events produce several pathological pain attenuation outcomes such as: (1) a decrease in the phosphorylation of voltage-gated sodium channels such as Nav1.7 leading to blunted neuronal excitability, (2) a reduction in microglial activation and microglia-related release of pro-inflammatory factors potentially resulting in reduced neuropathic pain, opioid-induced hypersensitivity, and diminished opioid tolerance, and (3) AMPK activation also normalizes dysregulation in mitochondrial and neuronal bioenergetics that is likely associated with diabetic neuropathic pain

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