A polyamine-deficient diet prevents oxaliplatin-induced acute cold and mechanical hypersensitivity in rats

PLoS One. 2013 Oct 30;8(10):e77828. doi: 10.1371/journal.pone.0077828. eCollection 2013.

Abstract

Background: Oxaliplatin is an anticancer drug used for the treatment of advanced colorectal cancer, but it can also cause painful peripheral neuropathies. The pathophysiology of these neuropathies has not been yet fully elucidated, but may involve spinal N-methyl-D-aspartate (NMDA) receptors, particularly the NR2B subunit. As polyamines are positive modulators of NMDA-NR2B receptors and mainly originate from dietary intake, the modulation of polyamines intake could represent an interesting way to prevent/modulate neuropathic pain symptoms by opposing glutamate neurotransmission.

Methods: The effect of a polyamine deficient diet was investigated in an animal model of oxaliplatin-induced acute pain hypersensitivity using behavioral tests (mechanical and cold hypersensitivity). The involvement of spinal glutamate neurotransmission was monitored by using a proton nuclear magnetic resonance spectroscopy based metabolomic approach and by assessing the expression and phosphorylation of the NR2B subunit of the NMDA receptor.

Results: A 7-day polyamine deficient diet totally prevented oxaliplatin-induced acute cold hypersensitivity and mechanical allodynia. Oxaliplatin-induced pain hypersensitivity was not associated with an increase in NR2B subunit expression or phosphorylation, but with an increase of glutamate level in the spinal dorsal horn which was completely prevented by a polyamine deficient diet. As a validation that the oxaliplatin-induced hypersensitivity could be due to an increased activity of the spinal glutamate system, an intrathecal administration of the specific NR2B antagonist, ifenprodil, totally reversed oxaliplatin-induced mechanical and cold hypersensitivity.

Conclusion: A polyamine deficient diet could represent a promising and valuable nutritional therapy to prevent oxaliplatin-induced acute pain hypersensitivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Animals
  • Antineoplastic Agents / toxicity
  • Behavior, Animal / drug effects*
  • Cold Temperature
  • Diet*
  • Glutamic Acid / metabolism
  • Hyperalgesia / chemically induced
  • Hyperalgesia / prevention & control*
  • Immunoblotting
  • Magnetic Resonance Spectroscopy
  • Male
  • Metabolomics
  • Neuralgia / chemically induced
  • Neuralgia / metabolism
  • Neuralgia / prevention & control*
  • Organoplatinum Compounds / toxicity*
  • Oxaliplatin
  • Phosphorylation
  • Piperidines / pharmacology
  • Polyamines / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Spinal Cord / drug effects
  • Spinal Cord / metabolism
  • Spinal Cord / pathology
  • Vasodilator Agents / pharmacology

Substances

  • Antineoplastic Agents
  • NR2B NMDA receptor
  • Organoplatinum Compounds
  • Piperidines
  • Polyamines
  • Receptors, N-Methyl-D-Aspartate
  • Vasodilator Agents
  • Oxaliplatin
  • Glutamic Acid
  • ifenprodil

Grant support

This work was supported by the University of Auvergne, INSERM and the local branch of the Ligue contre le Cancer [French league against cancer]. JF has received a PhD grant from the regional council of Auvergne and the European Community. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.