Abstract
Pain is an unpleasant sensory and emotional state that decreases quality of life. A metabolic sensor, adenosine monophosphate-activated protein kinase (AMPK), which is ubiquitously expressed in mammalian cells, has recently attracted interest as a new target of pain research. Abnormal AMPK expression and function in the peripheral and central nervous systems are associated with various types of pain. AMPK and its downstream kinases participate in the regulation of neuron excitability, neuroinflammation and axonal and myelin regeneration. Numerous AMPK activators have reduced pain behavior in animal models. The current understanding of pain has been deepened by AMPK research, but certain issues, such as the interactions of AMPK at each step of pain regulation, await further investigation. This review examines the roles of AMPK and its downstream kinases in neurons and non-neuronal cells, as well as their contribution to pain regulation.
Highlights
AMPK and Its Downstream Signals inThe International Association for the Study of Pain (IASP) revised the definition of pain in 2020, calling it “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage” [1]
A specific AMPK β subunit activator, A769662 [7], decreases neuronal hyperexcitability induced by pain-promoting endogenous mediators, such as nerve growth factor (NGF) in dorsal root ganglion (DRG)
Accumulating evidence indicates that AMPK plays important roles in pain modulation
Summary
The International Association for the Study of Pain (IASP) revised the definition of pain in 2020, calling it “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage” [1]. Adenosine monophosphate-activated protein kinase (AMPK) is an evolutionarily conserved serine/threonine enzyme that is ubiquitously expressed in mammalian cells and is described as a cellular fuel gauge [3] This kinase can be activated by many endogenous stimuli, such as metabolic stress (e.g., heat shock or hypoxia) [3], some hormones associated with lipometabolism and glycometabolism (e.g., adiponectin, leptin) [4,5], pharmacological compounds (e.g., 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) [6], A769662 [7], resveratrol [8]) and metformin [9]). Experimental animal and clinical studies have shown that AMPK activators exert analgesic effects [14] These pieces of evidence, provided support the notion that AMPK and its downstream molecules are key regulators of pathological pain and help us to examine the underlying molecular mechanisms
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