Yaksh T L, Dirig D M, Conway C M, Svensson C, Luo Z D, Isakson P C
Department of Anesthesiology, University of California, San Diego, La Jolla, California 92093-0818, USA.
J Neurosci. 2001 Aug 15;21(16):5847-53. doi: 10.1523/JNEUROSCI.21-16-05847.2001.
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 E(2) (PGE(2)). This intrathecally evoked release of spinal PGE(2) 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 PGE(2) 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.
蛋白质免疫印迹法显示，环氧化酶-1（COX-1）和环氧化酶-2（COX-2）在大鼠脊髓背角和腹角以及背根神经节中组成性表达。使用环氧化酶（COX）同工酶的选择性抑制剂，我们发现，在留置慢性鞘内导管的大鼠中，鞘内注射P物质（SP；20 nmol）或N-甲基-D-天冬氨酸（NMDA；2 nmol）引起的急性热痛觉过敏以及向爪中注射角叉菜胶诱导的热痛觉过敏，均被鞘内和全身给予的COX-2抑制剂所抑制。鞘内给药的效果具有剂量依赖性和立体特异性。相比之下，全身给予而非鞘内给予的COX-1抑制剂可减轻角叉菜胶诱发的热痛觉过敏，但对鞘内注射SP引起的痛觉过敏无论通过何种途径给药均无作用。使用鞘内环路透析导管时，我们发现鞘内注射SP会增强前列腺素E2（PGE2）的释放。全身给予非特异性COX抑制剂以及COX-2选择性抑制剂可减少鞘内诱发的脊髓PGE2释放，但COX-1选择性抑制剂则无此作用。给予能阻断SP和角叉菜胶诱发痛觉过敏的全身剂量时，COX-2抑制剂而非COX-1抑制剂可减少脊髓注射SP诱发的PGE2释放。因此，脊髓中组成性表达的COX-2而非COX-1是脊髓以及全身给予COX-2抑制剂产生急性抗痛觉过敏作用的重要因素。
