Pathological pain is an enormous medical problem that places a significant burden on patients
and can result from an injury that has long since healed or be due to an unidentifiable cause. Although
treatments exist, they often either lack efficacy or have intolerable side effects. More importantly,
they do not reverse the changes in the nervous system mediating pathological pain, and thus
symptoms often return when therapies are discontinued. Consequently, novel therapies are urgently
needed that have both improved efficacy and disease-modifying properties. Here we highlight an
emerging target for novel pain therapies, adenosine monophosphate-activated protein kinase (AMPK).
AMPK is capable of regulating a variety of cellular processes including protein translation, activity of other kinases, and
mitochondrial metabolism, many of which are thought to contribute to pathological pain. Consistent with these properties,
preclinical studies show positive, and in some cases disease-modifying effects of either pharmacological activation or genetic
regulation of AMPK in models of nerve injury, chemotherapy-induced peripheral neuropathy (CIPN), postsurgical
pain, inflammatory pain, and diabetic neuropathy. Given the AMPK-activating ability of metformin, a widely prescribed
and well-tolerated drug, these preclinical studies provide a strong rationale for both retrospective and prospective human
pain trials with this drug. They also argue for the development of novel AMPK activators, whether orthosteric, allosteric,
or modulators of events upstream of the kinase. Together, this review will present the case for AMPK as a novel therapeutic
target for pain and will discuss future challenges in the path toward development of AMPK-based pain therapeutics.