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The Journal of Neuroscience, August 15, 2001, 21(16):5847-5853
The Acute Antihyperalgesic Action of Nonsteroidal, Anti-Inflammatory Drugs and Release of Spinal Prostaglandin E2 Is Mediated by the Inhibition of Constitutive Spinal Cyclooxygenase-2 (COX-2) but not COX-1
Tony L. Yaksh1, David M. Dirig1, Charles M. Conway1, Camilla Svensson1, Z. David Luo1, and Peter C. Isakson2 1 Department of Anesthesiology, University of California, San Diego, La Jolla, California 92093-0818, and 2 Pharmacia Corporation, Research and Development, St. Louis, Missouri 63198
Western blots show the constitutive expression of COX-1 and COX-2 in the rat spinal dorsal and ventral horns and in the dorsal root ganglia. Using selective inhibitors of cyclooxygenase (COX) isozymes, we show that in rats with chronic indwelling intrathecal catheters the acute thermal hyperalgesia evoked by the spinal delivery of substance P (SP; 20 nmol) or NMDA (2 nmol) and the thermal hyperalgesia induced by the injection of carrageenan into the paw are suppressed by intrathecal and systemic COX-2 inhibitors. The intrathecal effects are dose-dependent and stereospecific. In contrast, a COX-1 inhibitor given systemically, but not spinally, reduced carrageenan-evoked thermal hyperalgesia but had no effect by any route with spinal SP hyperalgesia. Using intrathecal loop dialysis catheters, we showed that intrathecal SP would enhance the release of prostaglandin E2 (PGE2). This intrathecally evoked release of spinal PGE2 was diminished by systemic delivery of nonspecific COX and COX-2-selective inhibitors, but not a COX-1-selective inhibitor. Given at systemic doses that block SP- and carrageenan-evoked hyperalgesia, COX-2, but not COX-1, inhibitors reduced spinal SP-evoked PGE2 release. Thus, constitutive spinal COX-2, but not COX-1, is an important contributor to the acute antihyperalgesic effects of spinal as well as systemic COX-2 inhibitors.
Key words: cyclooxygenase inhibitor; intrathecal injection; thermal hyperalgesia; NK-1; substance P; NMDA; ibuprofen; SC-58125; SC-560
Copyright © 2001 Society for Neuroscience 0270-6474/01/21165847-07$05.00/0
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