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The Journal of Neuroscience, February 11, 2004, 24(6):1451-1458; doi:10.1523/JNEUROSCI.1517-03.2004

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

Lee Koetzner,¹ Xiao-Ying Hua,¹ Josephine Lai,³ Frank Porreca,^3,4 and Tony Yaksh^1,2

Departments of ¹Anesthesiology and ²Pharmacology, University of California, San Diego, La Jolla, California 92093, and Departments of ³Pharmacology and ⁴Anesthesiology, University of Arizona, Tucson, Arizona 85724

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.

Key words: dynorphin; NMDA; aspartate; glutamate; prostaglandin E₂; cyclooxygenase

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Received May 21, 2003; revised October 6, 2003; accepted December 5, 2003.

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