BLOCKADE OF TOLERANCE TO MORPHINE BUT NOT TO KAPPA-OPIOIDS BY A NITRIC-OXIDE SYNTHASE INHIBITOR
BLOCKADE OF TOLERANCE TO MORPHINE BUT NOT TO KAPPA-OPIOIDS BY A NITRIC-OXIDE SYNTHASE INHIBITOR
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DOI：
10.1073/pnas.90.11.5162
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发表时间：
1993-06-01
影响因子：
11.1
通讯作者：
PASTERNAK, GW
中科院分区：
文献类型：
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作者：
KOLESNIKOV, YA;PICK, CG;PASTERNAK, GW
一氧化氮合酶抑制剂N（G）-硝基-L-精氨酸（NO2 Arg）阻断小鼠吗啡耐受。植入吗啡颗粒后，镇痛反应从第一天的100%下降到第三天的0%。NO2 Arg与颗粒沿着共同给药显著延缓了耐受性的发展; 60%的小鼠在3天后镇痛，50%的小鼠在5天后镇痛。在每日注射范例中，对吗啡的镇痛反应在5天内从60%降低至0%。伴随施用吗啡沿着施用2 mg/kg/天剂量的NO2 Arg可防止耐受4周。单次NO2 Arg剂量延迟吗啡耐受数天，每4天给药几乎与每日NO2 Arg一样有效。尽管继续给予吗啡沿着NO2 Arg，但NO2 Arg在5天内缓慢逆转预先存在的耐受性。NO2 Arg还降低依赖性并逆转先前建立的依赖性。NO2 Arg不能阻止对kappa 1激动剂反式-3，4-二氯-N-甲基-N-[2-（1-吡咯烷基）环己基]-苯乙酰胺（U 50，488 H）或kappa 3药物纳洛酮苯甲酰腙介导的镇痛耐受，表明NO在mu耐受和依赖机制中的选择性作用。
The nitric oxide synthase inhibitor N(G)-nitro-L-arginine (NO2Arg) blocks morphine tolerance in mice. After implantation of morphine pellets the analgesic response decreases from 100% on the first day to 0% on the third. Coadministration of NO2Arg along with the pellets markedly retards the development of tolerance; 60% of mice are analgesic after 3 days, and 50% of mice are analgesic after 5 days. In a daily injection paradigm the analgesic response to morphine is reduced from 60% to 0% by 5 days. Concomitant administration of morphine along with NO2Arg at doses of 2 mg/kg per day prevents tolerance for 4 weeks. A single NO2Arg dose retards morphine tolerance for several days, and dosing every 4 days is almost as effective as daily NO2Arg. NO2Arg slowly reverses preexisting tolerance over 5 days despite the continued administration of morphine along with NO2Arg. NO2Arg also reduces dependence and reverses previously established dependence. NO2Arg does not prevent tolerance to analgesia mediated by the kappa1 agonist trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolindinyl)cyclohexyl]-benzene-acetamide (U50,488H) or the kappa3 agent naloxone benzoylhydrazone, indicating a selective action of NO in the mechanisms of mu tolerance and dependence.