The spinal phospholipase-cyclooxygenase-prostanoid cascade in nociceptive processing.
Intrathecal phospholipase A2 (PLA2) and cyclooxygenase-2 (COX-2), but not COX-1, inhibitors attenuate facilitated pain states generated by peripheral injury/inflammation and by direct activation of spinal glutamate and substance P receptors. These results are consistent with the constitutive expression of PLA2 and COX-2 in spinal cord, the spinal release of prostaglandins by persistent afferent input, and the effects of prostaglandins on spinal excitability. Whereas the acute actions of COX-2 inhibitors are clearly mediated by constitutively expressed spinal COX-2, studies of spinal COX-2 expression indicate that it is upregulated by neural input and circulating cytokines. Given the intrathecal potency of COX-2 inhibitors, the comparable efficacy of intrathecal versus systemic COX-2 inhibitors in hyperalgesic states not associated with inflammation, and the onset of antihyperalgesic activity prior to COX-2 upregulation, it is argued that a principal antihyperalgesic mechanism of COX-2 inhibitors lies with modulation of constitutive COX-2 present at the spinal level.
Svensson
Camilla I
CI
Department of Anesthesiology, University of California, San Diego, La Jolla, California 92093-0818, USA. csvensson@ucsd.edu
Yaksh
Tony L
TL
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D006801:Humans; D006930:Hyperalgesia; D010146:Pain / Q000503:physiopathology*; D010741:Phospholipases A / Q000502:physiology*; D054467:Phospholipases A2; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D011453:Prostaglandins / Q000502:physiology*; D015398:Signal Transduction; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D015533:Transcriptional Activation
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011453:Prostaglandins; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D054467:Phospholipases A2