Activities of 2-phthalimidethyl nitrate and 2-phthalimidethanol in the models of nociceptive response and edema induced by formaldehyde in mice and preliminary investigation of the underlying mechanisms
Activities of 2-phthalimidethyl nitrate and 2-phthalimidethanol in the models of nociceptive response and edema induced by formaldehyde in mice and preliminary investigation of the underlying mechanisms
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DOI：
10.1016/j.ejphar.2015.02.052
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发表时间：
2015-06-05
影响因子：
5
通讯作者：
Coelho, Marcio M.
中科院分区：
文献类型：
--
作者：
Godin, Adriana M.;Araujo, Debora P.;Coelho, Marcio M.
最近在疼痛和炎症模型中证实了2-邻苯二甲酰亚胺乙基硝酸酯（PTD-NO）和2-邻苯二甲酰亚胺乙醇（PTD-OH）的活性。我们扩大了我们的调查，通过评估他们的活动，在模型中的panciceplive和炎性疼痛和炎性水肿，PTD-NO的初步药代动力学参数和阿片类药物和大麻素途径的作用类似物的活动。经口（p.o.）在足底注射甲醛前1小时给予PTD-NO或PTD-OH，抑制了两个阶段的疼痛反应（500和750 mg/kg）和爪水肿（125，250，500和750 mg/kg）。在p.o. PTD-NO和PTD-OH的血浆峰浓度分别为0.92和1.13 h。PTD-NO的血浆浓度高于PTD-OH。腹膜内（i. p.）给予CB 1（AM 251）或CB 2（AM 630）大麻素受体拮抗剂（4或8 mg/kg，~ 30分钟）或阿片样物质拮抗剂纳洛酮（5或10 mg/kg，~ 30分钟）不影响类似物的抗伤害感受活性。AM251（8mg/kg，i.p.，-30分钟）减弱了两种类似物的抗水肿活性，而纳曲酮（10 mg/kg，i. p.，两种类似物的抗水肿活性不受CB 2大麻素拮抗剂AM 630（4或8 mg/kg，i. p.，约30分钟）。总之，我们通过显示这些邻苯二甲酰亚胺类似物在伤害性和炎性疼痛和炎性水肿模型中也表现出显著的活性，扩展了对PTD-NO和PTD-OH活性的认识。阿片类和大麻类机制部分介导抗炎，但不抗伤害活性。(C)2015 Elsevier B. V.版权所有。
The activities of 2-phthalimidethyl nitrate (PTD-NO) and 2-phthalimidethanol (PTD-OH) were recently demonstrated in models of pain and inflammation. We expanded our investigation by evaluating their activities in models of nociceplive and inflammatory pain and inflammatory edema, the preliminary pharmacokinetic parameter for PTD-NO and the role of opioid and cannabinoid pathways in the activity of analogs. Per os (p.o.) administration of PTD-NO or PTD-OH, 1 h before intraplantar injection of formaldehyde, inhibited both phases of the nociceplive response (500 and 750 mg/kg) and paw edema (125, 250, 500 and 750 mg/kg). After p.o. administration of PTD-NO, peak plasma concentrations of PTD-NO and PTD-OH were found 0.92 and 1.13 h, respectively. The plasma concentrations of PTD-NO were higher than those of PTD-OH. Intraperitoneal (i.p.) administration of CB1 (AM251) or CB2 (AM630) cannabinoid receptor antagonists (4 or 8 mg/kg, -30 min) or opioid antagonist naltrexone (5 or 10 mg/kg, -30 min) did not affect the antinociceptive activities of the analogs. AM251 (8 mg/kg, i.p., -30 min) attenuated the antiedematogenic activity of both analogs, while naltrexone (10 mg/kg, i.p., -30 min) only attenuated the antiedematogenic activity of PTD-NO. The antiedematogenic activities of both analogs were not affected by the CB2 cannabinoid antagonist AM630 (4 or 8 mg/kg, i.p., -30 min). Concluding, we expanded the knowledge on the activities of PTD-NO and PTD-OH by showing that these phthalimide analogs also exhibit marked activity in models of nociceptive and inflammatory pain and inflammatory edema. Opioid and cannabinoid mechanisms partially mediate the anti-inflammatory, but not the antinociceptive activity. (C) 2015 Elsevier B.V. All rights reserved.