Metabolic Connection of Inflammatory Pain: Pivotal Role of a Pyruvate Dehydrogenase Kinase-Pyruvate Dehydrogenase-Lactic Acid Axis

• DOI: 10.1523/jneurosci.1910-15.2015
• Publication Date: 2015-10-22T07:53:55Z
• Authors: Mithilesh Kumar Jha; Gyun Jee Song; Maan Gee Lee; Nam Ho Jeoung; Younghoon Go; Robert A. Harris; Dong Ho Park; Hyun Kook; In-Kyu Lee; Kyoungho Suk
• Keywords: PDK4; Pyruvic acid

Pyruvate dehydrogenase kinases (PDK1-4) are mitochondrial metabolic regulators that serve as decision makers via modulation of pyruvate (PDH) activity to convert either aerobically acetyl-CoA or anaerobically lactate. Metabolic dysregulation and inflammatory processes two sides the same coin in several pathophysiological conditions. The lactic acid surge associated with shift has been implicated diverse painful states. In this study, we investigated role PDK-PDH-lactic axis pathogenesis chronic pain. Deficiency Pdk2 and/or Pdk4 mice attenuated complete Freund's adjuvant (CFA)-induced pain hypersensitivities. Likewise, Pdk2/4 deficiency localized along hallmarks peripheral central inflammation following intraplantar administration CFA. vitro studies supported PDK2/4 promoters classical proinflammatory activation macrophages. Moreover, pharmacological inhibition PDKs production diminished CFA-induced Thus, a seems mediate inflammation-driven pain, establishing connection between metabolism pain.The (PDKs) their substrate PDH orchestrate conversion Lactate, predominant end product glycolysis, recently identified signaling molecule for neuron-glia interactions neuronal plasticity. Pathological subsequent thought play an important states; however, contribution is still be comprehended. Here, report constitutes key component pathogenesis. Our findings establish unanticipated link This study unlocks previously ill-explored research avenue control