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 Harris, Dong Ho Park, Hyun Kook, In Kyu Lee, Kyoungho Suk

Research output: Contribution to journalArticle

20 Citations (Scopus)

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

Fingerprint

Pyruvic Acid
Lactic Acid
Oxidoreductases
Pain
Freund's Adjuvant
Inflammation
Chronic Pain
Hypersensitivity
Acetyl Coenzyme A
Macrophage Activation
pyruvate dehydrogenase (acetyl-transferring) kinase
Pharmacology

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Metabolic connection of inflammatory pain : Pivotal role of a pyruvate dehydrogenase kinase-pyruvate dehydrogenase-lactic acid axis. / Jha, Mithilesh Kumar; Song, Gyun Jee; Lee, Maan Gee; Jeoung, Nam Ho; Go, Younghoon; Harris, Robert; Park, Dong Ho; Kook, Hyun; Lee, In Kyu; Suk, Kyoungho.

In: Journal of Neuroscience, Vol. 35, No. 42, 21.10.2015, p. 14353-14369.

Research output: Contribution to journalArticle

Jha, Mithilesh Kumar ; Song, Gyun Jee ; Lee, Maan Gee ; Jeoung, Nam Ho ; Go, Younghoon ; Harris, Robert ; Park, Dong Ho ; Kook, Hyun ; Lee, In Kyu ; Suk, Kyoungho. / Metabolic connection of inflammatory pain : Pivotal role of a pyruvate dehydrogenase kinase-pyruvate dehydrogenase-lactic acid axis. In: Journal of Neuroscience. 2015 ; Vol. 35, No. 42. pp. 14353-14369.
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