Inflammatory hyperalgesia induces essential bioactive lipid production in the spinal cord

J Neurochem. 2010 Aug;114(4):981-93. doi: 10.1111/j.1471-4159.2010.06815.x. Epub 2010 May 14.


Lipid molecules play an important role in regulating the sensitivity of sensory neurons and enhancing pain perception, and growing evidence indicates that the effect occurs both at the site of injury and in the spinal cord. Using high-throughput mass spectrometry methodology, we sought to determine the contribution of spinal bioactive lipid species to inflammation-induced hyperalgesia in rats. Quantitative analysis of CSF and spinal cord tissue for eicosanoids, ethanolamides and fatty acids revealed the presence of 102 distinct lipid species. After induction of peripheral inflammation by intra-plantar injection of carrageenan to the ipsilateral hind paw, lipid changes in cyclooxygenase (COX) and 12-lipoxygenase (12-LOX) signaling pathways peaked at 4 h in the CSF. In contrast, changes occurred in a temporally disparate manner in the spinal cord with LOX-derived hepoxilins followed by COX-derived prostaglandin E(2), and subsequently the ethanolamine anandamide. Systemic treatment with the mu opioid agonist morphine, the COX inhibitor ketorolac, or the LOX inhibitor nordihydroguaiaretic acid significantly reduced tactile allodynia, while their effects on the lipid metabolites were different. Morphine did not alter the lipid profile in the presence or absence of carrageenan inflammation. Ketorolac caused a global reduction in eicosanoid metabolism in naïve animals that remained suppressed following injection of carrageenan. Nordihydroguaiaretic acid-treated animals also displayed reduced basal levels of COX and 12-LOX metabolites, but only 12-LOX metabolites remained decreased after carrageenan treatment. These findings suggest that both COX and 12-LOX play an important role in the induction of carrageenan-mediated hyperalgesia through these pathways.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Arachidonate 12-Lipoxygenase / cerebrospinal fluid
  • Arachidonate 12-Lipoxygenase / physiology
  • Cannabinoid Receptor Modulators / cerebrospinal fluid
  • Cannabinoid Receptor Modulators / physiology
  • Eicosanoids / cerebrospinal fluid
  • Eicosanoids / physiology
  • Ethanolamines / cerebrospinal fluid
  • Ethanolamines / pharmacology
  • Fatty Acids / cerebrospinal fluid
  • Fatty Acids / physiology
  • Hyperalgesia / cerebrospinal fluid
  • Hyperalgesia / metabolism*
  • Hyperalgesia / pathology*
  • Inflammation Mediators / pharmacology
  • Inflammation Mediators / physiology*
  • Lipids / biosynthesis*
  • Lipids / cerebrospinal fluid
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Spinal Cord / metabolism*
  • Spinal Cord / pathology*


  • Cannabinoid Receptor Modulators
  • Eicosanoids
  • Ethanolamines
  • Fatty Acids
  • Inflammation Mediators
  • Lipids
  • Arachidonate 12-Lipoxygenase