Local peripheral antinociceptive effects of 14-O-methyloxymorphone derivatives in inflammatory and neuropathic pain in the rat
Local peripheral antinociceptive effects of 14-O-methyloxymorphone derivatives in inflammatory and neuropathic pain in the rat
复制标题
DOI：
10.1016/j.ejphar.2006.11.037
复制
发表时间：
2007-03-06
影响因子：
5
通讯作者：
Przewlocka, Barbara
中科院分区：
文献类型：
--
作者：
Obara, Ilona;Makuch, Wioletta;Przewlocka, Barbara
阿片类药物外周给药后实现的抗伤害感受为治疗严重和慢性疼痛开辟了一条新途径。此外，限制进入中枢神经系统的阿片类镇痛药可提高阿片类药物在临床实践中使用的安全性。在本研究中，6-氨基酸取代的衍生物的14-O-甲氧基吗啡酮的抗伤害性作用的外周成分进行了研究后，局部足底（i.pl.）在炎症性和神经性疼痛的大鼠模型中施用。它们的抗伤害活性进行了比较与吗啡，经典的p-阿片受体激动剂。吗啡和6-氨基酸衍生物的腹腔内给药产生福尔马林诱导的发炎爪退缩的剂量依赖性减少，对爪水肿没有显著影响。当地i.pl.在患有由坐骨神经结扎诱导的神经病理性疼痛的大鼠中给予新衍生物产生抗异常性疼痛和抗痛觉过敏作用;然而，抗伤害感受活性低于在炎性疼痛中观察到的活性。在这两种模型中，在i.pl.给药是全身性（s.c.）活性低得多，表明抗伤害感受作用是由于局部作用。此外，局部阿片类镇痛作用显着减弱纳洛酮甲碘，外周作用阿片受体拮抗剂，表明该作用是由外周阿片受体介导的。本数据表明，14-0-甲氧基吗啡酮的外周限制性6-氨基酸缀合物在局部给药后引起抗伤害感受，在炎症性疼痛中比在神经性疼痛中更有效。具有外周作用位点的阿片类药物可以是治疗持久疼痛的重要靶点。(c)2006 Elsevier B. V.保留所有权利。
Antinociception achieved after peripheral administration of opioids has opened a new approach to the treatment of severe and chronic pain. Additionally, opioid analgesics with restricted access to the central nervous system could improve safety of opioid drugs used in clinical practice. In the present study, peripheral components of antinociceptive actions of 6-amino acid-substituted derivatives of 14-O-methyloxymorphone were investigated after local intraplantar (i.pl.) administration in rat models of inflammatory and neuropathic pain. Their antinociceptive activities were compared with those of morphine, the classical p-opioid receptor agonist. Intraplamar administration of morphine and the 6-amino acid derivatives produced dose-dependent reduction of formalin-induced flinching of the inflamed paw, without significant effect on the paw edema. Local i.pl. administration of the new derivatives in rats with neuropathic pain induced by sciatic nerve ligation produced antiallodynic and antiltyperalgesic effects; however, the antinociceptive activity was lower than that observed in inflammatory pain. In both models, the 6-amino acid derivatives and morphine at doses that produced analgesia after i.pl. administration were systemically (s.c.) much less active indicating that the antinociceptive action is due to a local effect. Moreover, the local opioid antinociceptive effects were significantly attenuated by naloxone methiodide, a peripherally acting opioid receptor antagonist, demonstrating that the effect was mediated by peripheral opioid receptors. The present data indicate that the peripherally restricted 6-amino acid conjugates of 14-0-methyloxymorphone elicit antinociception after local administration, being more potent in inflammatory than in neuropathic pain. Opioid drugs with peripheral site of action can be an important target for the treatment of long lasting pain. (c) 2006 Elsevier B.V. All rights reserved.