The intraperitoneal administration of MOTS-c produces antinociceptive and anti-inflammatory effects through the activation of AMPK pathway in the mouse formalin test

Eur J Pharmacol. 2020 Mar 5:870:172909. doi: 10.1016/j.ejphar.2020.172909. Epub 2020 Jan 8.

Abstract

The activation of the AMP activated protein kinase (AMPK) exerts antinociceptive effects in acute and neuropathic pain models. Mitochondrial open-reading-frame of the twelve S rRNA-c (MOTS-c), a mitochondrial-derived peptide, regulates many biological activities via activating AMPK. However, the role of MOTS-c in the formalin-induced inflammatory nociception remains unclear. In this study, we investigated the role of MOTS-c in the formalin-induced inflammatory nociception. The antinociceptive effect of MOTS-c was assessed by recording the time spent licking paw. The anti-inflammatory effect of MOTS-c was evaluated by detecting the inflammatory cytokine level changes in the mouse serum. Western blot was used to detect the changes of protein phosphorylation levels in the mouse spinal cord. Changes of c-fos expression in the spinal cord were assessed by immunohistochemistry. Our results showed that the intraperitoneal administration of MOTS-c reduced the time spent on licking in phase 2 in a dose-dependent manner in the formalin test. The antinociceptive effects of MOTS-c (50 mg/kg, i.p.) were attenuated by the AMPK antagonist compound C (10 mg/kg, i.p.). MOTS-c (50 mg/kg, i.p.) significantly reduced pro-inflammatory cytokine levels and elevated the level of anti-inflammatory cytokine in mouse serum. In addition, MOTS-c treatment significantly increased AMPKα phosphorylation level and suppressed formalin-induced extracellular signal-regulated kinase (ERK), c-Jun amino-terminal kinases (JNK), and P38 activation and c-fos expression in the mouse spinal cord. These results suggest that systemic administration of MOTS-c exerts antinociceptive and anti-inflammatory effects, at least partially, through activating AMPK pathway and inhibiting MAP kinases-c-fos signaling pathway in the mouse formalin test.

Keywords: AMP activated protein kinase; Anti-inflammation; Antinociception; Formalin test; MOTS-C.

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Analgesics / administration & dosage*
  • Animals
  • Anti-Inflammatory Agents / administration & dosage*
  • Cytokines / metabolism
  • Enzyme Activation / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Formaldehyde / metabolism
  • Gene Expression Regulation, Enzymologic
  • Humans
  • Injections, Intraperitoneal
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • MAP Kinase Signaling System
  • Male
  • Mice
  • Mice, Inbred ICR
  • Mitochondrial Proteins / administration & dosage*
  • Neuralgia / metabolism*
  • Nociception / drug effects
  • Pain Measurement
  • Phosphorylation
  • Proto-Oncogene Proteins c-fos / metabolism
  • Spinal Cord / drug effects
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Analgesics
  • Anti-Inflammatory Agents
  • Cytokines
  • MOTS-c peptide, human
  • Mitochondrial Proteins
  • Proto-Oncogene Proteins c-fos
  • Formaldehyde
  • Extracellular Signal-Regulated MAP Kinases
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • AMP-Activated Protein Kinases