INVOLVEMENT OF NITRIC OXIDE IN MAINTAINING AND FACILITATING THE HYPERALGESIA ASSOCIATED WITH CHRONIC NOCICEPTION IN THE SITE OF THE FIRST SYNAPTIC RELAY OF THE PAIN PATHWAY

为了阐明脊髓伤害性反应过程中一氧化氮的参与，在佐剂或热诱导的炎症后，分析了大鼠腰椎背角中热退缩潜伏期与一氧化氮合酶染色神经元的相关性。在后爪皮下注射完全弗氏佐剂后4小时至5天，在对受影响区域施加热刺激后观察到显著的热痛觉过敏。在对照组大鼠中，NADPH-黄递酶阳性神经元观察到在椎板I至V与更高的密度在椎板II和III之间的边界在腰脊髓背角，它们也被染色化学大鼠小脑一氧化氮合酶。NADPH-黄递酶和一氧化氮合酶阳性神经元显着增加，在同侧的背角浅层的炎症后爪在第3天的促炎剂诱导的炎症。NADPH-黄递酶阳性神经元在致炎1小时和1天，或热致炎1小时、1天和3天（47 ℃，30分钟）时未观察到变化。静脉注射一氧化氮合酶拮抗剂N ^-L-精氨酸甲酯（LNAME，50 mg/kg），在炎症第3天显著阻断了消炎药诱导的热痛觉过敏，但在第1天没有，并且对非炎症大鼠没有影响。<omega>LNAME在炎症第3天的这种抗痛觉过敏作用被预先给予L-精氨酸（500 mg/kg i.p.）逆转，这些数据表明，在疼痛通路的第一突触中继部位的一氧化氮产生神经元参与维持和促进与慢性伤害感受相关的痛觉过敏。

In order to elucidate the involvement of nitric oxide in spinal nociceptive processing, a correlation of thermal withdrawal latency with nitric oxide synthase-stained neurons in the rat lumbar dorsal horn was analyzed after adjuvant- or heat-induced inflammation. From 4 hrs through 5 days after subcutaneous injection of complete Freund's adjuvant into the hind paw, a marked thermal hyperalgesia was observed following heat stimulus applied to the affected region. In control rats, NADPH-diaphorase-positive neurons were observed in laminae I through V with a higher density at the border between laminae II and III in the lumbar spinal dorsal horn, and they were also stained immunohistochemically for rat cerebellar nitric oxide synthase. NADPH-diaphorase- and nitric oxide synthase-positive neurons increased significantly in the superficial layrs of the dorsal horn ipsilateral to the inflamend hind paw at day 3 of adjuvant-induced inflammation. No change in NADPH-diaphorase-positive neurons was observed at 1 hr and 1 day of adjuvant-induced inflammation, or at 1 hr, 1 and 3 days of heat-induced inflammation (47ﾟC for 30 min). The intravenous administration of N^<omega>-L-arginine methyl ester (LNAME,50 mg/kg), an antagonist of nitric oxide synthase, significantly blocked the adjuvant-induced thermal hyperalgesia at day 3 of inflammation, but not at day 1, and had no effect in non-inflamed rats. This anti-hyperalgesic effect of LNAME at day 3 of inflammation was reversed by the priodministration of L-arginine (500 mg/kg i.p.), a substrate of nitric oxide synthase.These data suggest that nitric oxide producing neurons in the site of the first synaptic relay of the pain pathway are involved in maintaining and facilitating the hyperalgesia associated with chronic nociception.