title: AMPKα1 knockout enhances nociceptive behaviors and spinal glutamatergic synaptic activities via production of reactive oxygen species in the spinal dorsal horn.
abstract: Emerging studies have shown that pharmacological activation of adenosine monophosphate-activated protein kinase (AMPK) produces potent analgesic effects in different animal pain models. Currently, the spinal molecular and synaptic mechanism by which AMPK regulates the pain signaling system remains unclear. To address this issue, we utilized the Cre-LoxP system to conditionally knockout the AMPKα1 gene in the nervous system of mice. We demonstrated that AMPKα1 is imperative for maintaining normal nociception, and mice deficient for AMPKα1 exhibit mechanical allodynia. This is concomitantly associated with increased glutamatergic synaptic activities in neurons located in the superficial spinal dorsal horn, which results from the increased glutamate release from presynaptic terminals and function of ligand-gated glutamate receptors at the postsynaptic neurons. Additionally, AMPKα1 knockout mice have increased activities of extracellular signal-regulated kinases (ERK) and p38 mitogen-activated protein kinases (p38), as well as elevated levels of interleukin-1β (IL-1β), reactive oxygen species (ROS), and heme oxygenase 1 (HO-1) in the spinal dorsal horn. Systemic administration of a non-specific ROS scavenger (phenyl-N-tert-butylnitrone, PBN) or a HO-1 activator (Cobalt protoporphyrin IX, CoPP) attenuated allodynia in AMPKα1 knockout mice. Bath-perfusion of the ROS scavenger or HO-1 activator effectively attenuated the increased ROS levels and glutamatergic synaptic activities in the spinal dorsal horn. Our findings suggest that ROS are the key down-stream signaling molecules mediating the behavioral hypersensitivity in AMPKα1 knockout mice. Thus, targeting AMPKα1 may represent an effective approach for the treatment of pathological pain conditions associated with neuroinflammation at the spinal dorsal horn.
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, The University of Georgia College of Pharmacy, Athens, Georgia 30602, USA.
authors.forename: Dylan W
authors.initials: DW
authors.lastname: Maixner
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, The University of Georgia College of Pharmacy, Athens, Georgia 30602, USA.|Department of Cardiovascular Medicine, The Third Hospital of Wuhan, Wuhan 430074, Hubei Province, China.|Department of Endocrinology and Metabolism, Shanghai Tenth People's hospital, Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: Xisheng
authors.initials: X
authors.lastname: Yan
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, The University of Georgia College of Pharmacy, Athens, Georgia 30602, USA.
authors.forename: Shelley B
authors.initials: SB
authors.lastname: Hooks
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, The University of Georgia College of Pharmacy, Athens, Georgia 30602, USA.
authors.forename: Han-Rong
authors.initials: HR
authors.lastname: Weng
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004660:Encephalitis / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D018698:Glutamic Acid / Q000502:physiology*; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006930:Hyperalgesia / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D059225:Nociception / Q000502:physiology*; D017729:Presynaptic Terminals / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D066148:Spinal Cord Dorsal Horn / Q000378:metabolism*
chemical_list: D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D053583:Interleukin-1beta; D017382:Reactive Oxygen Species; C029217:phenyl-N-tert-butylnitrone; D018698:Glutamic Acid; D051547:Heme Oxygenase-1; C548179:Prkaa1 protein, mouse; D055372:AMP-Activated Protein Kinases
keywords: AMPK; ROS; cytokines; glutamatergic synapses; nociception; patch clamp