Malmberg Annika B, Yaksh Tony L
Department of Anesthesiology, University of California San Diego, La Jolla, CA 92093 USA Department of Clinical Pharmacology, Sahlgrenska University Hospital, Göteborg Sweden.
Pain. 1993 Sep;54(3):291-300. doi: 10.1016/0304-3959(93)90028-N.
To assess the possible role of spinal nitric oxide (NO) synthesis in nociceptive processing, we examined the effect of intrathecal (i.t.) injection of arginine analogs that act as alternate substrates for NO synthase and thus inhibit NO production. NG-nitro-L-arginine ester (r-NAME) and NG-monomethyl-L-arginine (L-NMMA) produced a dose-dependent, stereospecific inhibition of the second phase (10-60 min; ED50, 135 and 246 nmol) of the formalin test with minimal effect on the first phase (0-9 min; ED50 > 1.1 mumol). The inhibitory action of L-NAME was dose-dependently reversed by i.t. L-arginine (ID50, 4.9 mumol) but not by D-arginine (ID50 > 14 mumol). The suppression of the second-phase formalin response by L-NAME was similar whether administered before or after formalin injection into the rat paw. Spinal administration of L-NAME (370 nmol), but not D-NAME (3.7 mumol), also blocked thermal hyperalgesia induced by i.t. injection of N-methyl-D-aspartate (NMDA; 6.8 nmol). The effect of L-NAME was reversed by L-arginine (4.7 mumol) but not with D-arginine (14 mumol). None of the compounds, L-NAME, D-NAME or L-arginine, when injected alone, had any effect on normal thermal response latencies or on the 52.5 degrees C hot plate. These studies indicate that modulation of spinal NO synthesis can diminish the facilitated processing of afferent activity which is induced by a continued afferent barrage (second phase of the formalin test). This hyperalgesic component appears initiated by the activation of a spinal NMDA receptor that, through the generation of NO, leads to the observed augmented processing of afferent input and the associated hyperalgesic component of the subsequent pain behavior.
为评估脊髓一氧化氮（NO）合成在伤害性信息处理中的可能作用，我们研究了鞘内注射精氨酸类似物的效果，这些类似物作为NO合酶的替代底物，从而抑制NO的产生。NG-硝基-L-精氨酸酯（r-NAME）和NG-单甲基-L-精氨酸（L-NMMA）对福尔马林试验的第二阶段（10 - 60分钟；半数有效剂量[ED50]，135和246纳摩尔）产生剂量依赖性、立体特异性抑制，而对第一阶段（0 - 9分钟；ED50 > 1.1微摩尔）影响极小。L-NAME的抑制作用可被鞘内注射L-精氨酸（半数有效剂量[ID50]，4.9微摩尔）剂量依赖性逆转，但不能被D-精氨酸（ID50 > 14微摩尔）逆转。无论在福尔马林注射到大鼠爪部之前还是之后给予L-NAME，其对福尔马林试验第二阶段反应的抑制作用相似。鞘内给予L-NAME（370纳摩尔），而非D-NAME（3.7微摩尔），也可阻断鞘内注射N-甲基-D-天冬氨酸（NMDA；6.8纳摩尔）诱导的热痛觉过敏。L-NAME的作用可被L-精氨酸（4.7微摩尔）逆转，但不能被D-精氨酸（14微摩尔）逆转。单独注射L-NAME、D-NAME或L-精氨酸时，这些化合物对正常热反应潜伏期或52.5℃热板均无任何影响。这些研究表明，脊髓NO合成的调节可减少由持续传入冲动（福尔马林试验第二阶段）诱导的传入活动的易化处理。这种痛觉过敏成分似乎由脊髓NMDA受体的激活引发，该受体通过产生NO导致观察到的传入输入的增强处理以及随后疼痛行为相关的痛觉过敏成分。
