Metabolic connection of inflammatory pain: Pivotal role of a pyruvate dehydrogenase kinase-pyruvate dehydrogenase-lactic acid axis

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

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Pyruvate dehydrogenase kinases (PDK1–4) are mitochondrial metabolic regulators that serve as decision makers via modulation of pyruvate dehydrogenase (PDH) activity to convert pyruvate either aerobically to acetyl-CoA or anaerobically to lactate. Metabolic dysregulation and inflammatory processes are two sides of the same coin in several pathophysiological conditions. The lactic acid surge associated with the metabolic shift has been implicated in diverse painful states. In this study, we investigated the role of PDKPDH-lactic acid axis in the pathogenesis of chronic inflammatory pain. Deficiency of Pdk2 and/or Pdk4 in mice attenuated complete Freund’s adjuvant (CFA)-induced pain hypersensitivities. Likewise, Pdk2/4 deficiency attenuated the localized lactic acid surge along with hallmarks of peripheral and central inflammation following intraplantar administration of CFA. In vitro studies supported the role of PDK2/4 as promoters of classical proinflammatory activation of macrophages. Moreover, the pharmacological inhibition of PDKs or lactic acid production diminished CFA-induced inflammation and pain hypersensitivities. Thus, a PDK-PDH-lactic acid axis seems to mediate inflammation-driven chronic pain, establishing a connection between metabolism and inflammatory pain.

Original languageEnglish (US)
Pages (from-to)14353-14369
Number of pages17
JournalJournal of Neuroscience
Volume35
Issue number42
DOIs
StatePublished - Oct 21 2015

Keywords

  • Chronic inflammatory pain
  • Inflammation
  • Macrophages
  • Metabolism
  • PDK-PDH lactic acid axis
  • Pain

ASJC Scopus subject areas

  • Neuroscience(all)

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