title: Pyruvate dehydrogenase kinase 2 and 4 gene deficiency attenuates nociceptive behaviors in a mouse model of acute inflammatory pain.
abstract: Pyruvate dehydrogenase (PDH) kinases (PDKs) 1-4, expressed in peripheral and central tissues, regulate the activity of the PDH complex (PDC). The PDC is an important mitochondrial gatekeeping enzyme that controls cellular metabolism. The role of PDKs in diverse neurological disorders, including neurometabolic aberrations and neurodegeneration, has been described. Implications for a role of PDKs in inflammation and neurometabolic coupling led us to investigate the effect of genetic ablation of PDK2/4 on nociception in a mouse model of acute inflammatory pain. Deficiency in Pdk2 and/or Pdk4 in mice led to attenuation of formalin-induced nociceptive behaviors (flinching, licking, biting, or lifting of the injected paw). Likewise, the pharmacological inhibition of PDKs substantially diminished the nociceptive responses in the second phase of the formalin test. Furthermore, formalin-provoked paw edema formation and mechanical and thermal hypersensitivities were significantly reduced in Pdk2/4-deficient mice. Formalin-driven neutrophil recruitment at the site of inflammation, spinal glial activation, and neuronal sensitization were substantially lessened in the second or late phase of the formalin test in Pdk2/4-deficient animals. Overall, our results suggest that PDK2/4 can be a potential target for the development of pharmacotherapy for the treatment of acute inflammatory pain. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Pharmacology, Brain Science and Engineering Institute, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
authors.forename: Mithilesh Kumar
authors.initials: MK
authors.lastname: Jha
authors.affiliation: Department of Pharmacology, Brain Science and Engineering Institute, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
authors.forename: Md Habibur
authors.initials: MH
authors.lastname: Rahman
authors.affiliation: Department of Ophthalmology, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
authors.forename: Dong Ho
authors.initials: DH
authors.lastname: Park
authors.affiliation: Department of Pharmacology, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Hyun
authors.initials: H
authors.lastname: Kook
authors.affiliation: Department of Internal Medicine, Division of Endocrinology and Metabolism, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
authors.affiliation: School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Won-Ha
authors.initials: WH
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, Brain Science and Engineering Institute, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
authors.forename: Kyoungho
authors.initials: K
authors.lastname: Suk
mesh_terms: D059787:Acute Pain / Q000235:genetics* / Q000523:psychology*; D000818:Animals; D001522:Behavior, Animal; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007249:Inflammation / Q000235:genetics* / Q000523:psychology*; D008262:Macrophage Activation / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009457:Neuroglia; D020556:Neutrophil Infiltration / Q000235:genetics; D059225:Nociception; D010147:Pain Measurement; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D013116:Spinal Cord / Q000473:pathology
chemical_list: D004791:Enzyme Inhibitors; C000631435:Pdk2 protein, mouse; C000631439:Pdk4 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017346:Protein Serine-Threonine Kinases
keywords: PDK; acute inflammation; formalin; nociceptive behaviors; pain