Adenosine Monophosphate-activated Protein Kinase (AMPK) Activators For the Prevention, Treatment and Potential Reversal of Pathological Pain

Abstract

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.

Pharmacological activation of AMPK inhibits incision-evoked mechanical hypersensitivity and the development of hyperalgesic priming in mice

“…Our in vitro experiments on DRG neurons indicate the combination of resveratrol and metformin activate AMPK in at least an additive fashion. These data add to a growing body of evidence that AMPK activation can inhibit the development of acute mechanical hypersensitivity resulting from injury (Melemedjian et al, 2011, Tillu et al, 2012a, Russe et al, 2013, Bullon et al, 2015, Ma et al, 2015, Song et al, 2015, Maixner et al, 2016, Ling et al, 2017), reduce the excitability of nociceptors (Melemedjian et al, 2011, Tillu et al, 2012a, Melemedjian et al, 2013, Asiedu et al, 2017) and prevent the development of hyperalgesic priming (Price and Dussor, 2013, Price et al, 2015, Asiedu et al, 2016, Mejia et al, 2016). We conclude that topical resveratrol and co-treatment of various AMPK activators such as metformin are clinically relevant and could show utility as pain therapeutics in humans.…”

Beyond symptomatic relief for chemotherapy‐induced peripheral neuropathy: Targeting the source

“…Recent preclinical studies have suggested that metformin, a drug approved by the US Food and Drug Administration (FDA) for glycemic control in patients with type 2 diabetes, alleviates neuropathic and inflammatory pain in various models . We demonstrated that metformin also prevents cisplatin‐induced neuropathic pain, numbness, and loss of IENFs .…”

Ion channels and neuronal hyperexcitability in chemotherapy-induced peripheral neuropathy

“…Indeed, there are indications that these agents may mediate their effects through other cellular signaling pathways including those that involve pro-inflammatory cytokines, protein kinases, growth factors, and reactive oxygen species (ROS). 15,73,121,142,143 …”