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.