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.
- Prostaglandin E
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