Larson A A, Kovacs K J, Cooper J C, Kitto K F
Graduate Program in Neuroscience, Department of Veterinary Pathobiology, University of Minnesota, St. Paul 55108, USA.
Pain. 2000 May;86(1-2):103-11. doi: 10.1016/s0304-3959(00)00236-0.
A single injection of nitric oxide (NO) synthase (NOS) inhibitors prevents the development of persistent hyperalgesia induced by various manipulations, suggesting that NO precipitates long-term changes in nociception. We examined the possibility that inhibition of NOS may also be sufficient to produce long-term decreases in nociceptive assays, such as writhing, that are known to be sensitive to the short-term effects of NOS inhibitors. We characterized short- and long-term effects of NOS inhibitors, N(omega)-nitro-L-arginine (L-NAME) or 7-nitro indazole (7-NI) injected intrathecally (i.t.) in mice on acetic acid-induced writhing. Doses of L-NAME that had no effect on hot plate or tail flick latencies inhibited writhing (0. 01-30 nmol) as well as spinal nNOS activity (5 and 100 nmol) when injected i.t. 60-90 min before testing. Anti-nociception was not mimicked by D-NAME but was prevented by co-administration with the NO precursor, L-arginine. Injection i.t. of 7-NI (30 min), a selective inhibitor of neuronal NOS (nNOS), inhibited NOS activity in the spinal cord and produced anti-nociception, confirming that writhing is sensitive to inhibition of nNOS. Although the acute action of both NOS inhibitors dissipated completely by 3-6 h, a delayed and prolonged inhibition of writhing was again observed 24 h after L-NAME (5-100 nmol), a time when spinal NOS activity was no longer inhibited by L-NAME (5 and 100 nmol) or 7-NI (25 nmol). This novel effect appears to be initiated by the transient inhibition of nNOS as delayed anti-nociception was mimicked by 7-NI at doses (10-100 nmol) that no longer inhibited spinal nNOS (25 nmol) at 24 h. Co-administration with L-arginine prevented the delayed (24 h) anti-nociceptive effects of L-NAME (30 nmol). L-Arginine (30 and 100 nmol) was without effect on nociception when administered alone 60 min or 24 h prior to testing. Together these data indicate that brief changes in the activity of nNOS induce both long- as well as short-term changes in nociception.
单次注射一氧化氮（NO）合酶（NOS）抑制剂可预防由各种操作诱导的持续性痛觉过敏的发展，这表明NO引发了痛觉感受的长期变化。我们研究了抑制NOS也可能足以使诸如扭体反应等痛觉测定产生长期降低的可能性，已知扭体反应对NOS抑制剂的短期作用敏感。我们对鞘内注射（i.t.）NOS抑制剂N（ω）-硝基-L-精氨酸（L-NAME）或7-硝基吲唑（7-NI）对小鼠醋酸诱导扭体反应的短期和长期影响进行了表征。在测试前60 - 90分钟鞘内注射时，对热板或甩尾潜伏期无影响的L-NAME剂量（0.01 - 30 nmol）可抑制扭体反应（5和100 nmol时也可抑制脊髓nNOS活性）。D-NAME不能模拟抗伤害感受作用，但与NO前体L-精氨酸共同给药可阻止其作用。鞘内注射7-NI（30分钟），一种神经元NOS（nNOS）的选择性抑制剂，可抑制脊髓中的NOS活性并产生抗伤害感受作用，证实扭体反应对nNOS的抑制敏感。尽管两种NOS抑制剂的急性作用在3 - 6小时内完全消散，但在L-NAME（5 - 100 nmol）注射24小时后再次观察到扭体反应的延迟和延长抑制，此时脊髓NOS活性不再被L-NAME（5和100 nmol）或7-NI（25 nmol）抑制。这种新效应似乎是由nNOS的短暂抑制引发的，因为在24小时时不再抑制脊髓nNOS（25 nmol）的7-NI剂量（10 - 100 nmol）可模拟延迟的抗伤害感受作用。与L-精氨酸共同给药可阻止L-NAME（30 nmol）的延迟（24小时）抗伤害感受作用。在测试前60分钟或24小时单独给予L-精氨酸（30和100 nmol）对痛觉感受无影响。这些数据共同表明，nNOS活性的短暂变化可诱导痛觉感受的长期和短期变化。
