Nonopioid Actions of Intrathecal Dynorphin Evoke Spinal Excitatory Amino Acid and Prostaglandin E2 Release Mediated by Cyclooxygenase-1 and -2

Lee Koetzner, Xiao Ying Hua, Josephine Lai, Frank Porreca, Tony Yaksh

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

Abstract

Spinal dynorphin is hypothesized to contribute to the hyperalgesia that follows tissue and nerve injury or sustained morphine exposure. We considered that these dynorphin actions are mediated by a cascade involving the spinal release of excitatory amino acids and prostaglandins. Unanesthetized rats with lumbar intrathecal injection and loop dialysis probes received intrathecal NMDA, dynorphin A(1-17), or dynorphin A(2-17). These agents elicited an acute release of glutamate, aspartate, and taurine but not serine. The dynorphin peptides and NMDA also elicited a long-lasting spinal release of prostaglandin E2. Prostaglandin release evoked by dynorphin A( 2-17) or NMDA was blocked by the NMDA antagonist amino-5-phosphonovalerate as well the cyclooxygenase (COX) inhibitor ibuprofen. To identify the COX isozyme contributing to this release, SC 58236, a COX-2 inhibitor, was given and found to reduce prostaglandin E2 release evoked by either agent. Unexpectedly, the COX-1 inhibitor SC 58560 also reduced dynorphin A(2-17)-induced, but not NMDA-induced, release of prostaglandin E2. These findings reveal a novel mechanism by which elevated levels of spinal dynorphin seen in pathological conditions may produce hyperalgesia through the release of excitatory amino acids and in part by the activation of a constitutive spinal COX-1 and -2 cascade.

Original languageEnglish (US)
Pages (from-to)1451-1458
Number of pages8
JournalJournal of Neuroscience
Volume24
Issue number6
DOIs
StatePublished - Feb 11 2004

Keywords

  • Aspartate
  • Cyclooxygenase
  • Dynorphin
  • Glutamate
  • NMDA
  • Prostaglandin E

ASJC Scopus subject areas

  • Neuroscience(all)

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