Co-administration of δ- and μ-opioid receptor agonists promotes peripheral opioid receptor function.
Co-administration of δ- and μ-opioid receptor agonists promotes peripheral opioid receptor function.
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DOI：
10.1016/j.pain.2010.09.009
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发表时间：
2010-12
期刊：
影响因子：
7.4
通讯作者：
Honda CN
中科院分区：
文献类型：
--
作者：
Schramm CL;Honda CN
在动物模型中，组织损伤或炎症后外周阿片类镇痛的增强是有据可查的，但外周阿片类治疗的临床结果仍然不一致。先前在中枢神经系统中的研究表明，μ-和δ-阿片受体激动剂的联合给药可以增强镇痛效果;然而，对外周阿片受体相互作用的功能后果知之甚少。本研究探讨了足底注射μ-和δ-阿片受体激动剂吗啡和deltorphin单独和联合对幼稚大鼠伤害性感受行为试验和钾诱发幼稚大鼠坐骨神经CGRP释放的影响。两种药物都不单独影响伤害性行为或CGRP释放。两种药物联合给药后，机械伤害敏感性的两个单独测量值保持不变。相比之下，当deltorphin与吗啡共注射时，观察到剂量依赖性和外周限制性的增加，在缩爪lavenia到辐射热。同样，浓度依赖性抑制CGRP的释放时，观察到deltorphin和吗啡在钾刺激前顺序给药。然而，没有观察到抑制时，吗啡给药前deltorphin。所有阿片类药物的联合作用均被拮抗剂的联合应用阻断。Deltorphin暴露还增强了另一种μ-阿片受体激动剂DAMGO的体内和体外作用。总之，这些结果表明，在正常条件下，δ-阿片受体激动剂增强μ-阿片受体激动剂在外周中的作用，并且δ-和μ-阿片受体激动剂的局部共同施用可改善外周阿片治疗用于治疗疼痛的结果。
Enhancement of peripheral opioid analgesia following tissue injury or inflammation in animal models is well-documented, but clinical results of peripheral opioid therapy remain inconsistent. Previous studies in the central nervous system have shown that co-administration of μ- and δ-opioid receptor agonists can enhance analgesic outcomes; however, less is known about the functional consequences of opioid receptor interactions in the periphery. The present study examines the effects of intraplantar injection of the μ- and δ-opioid receptor agonists, morphine and deltorphin, alone and in combination on behavioral tests of nociception in naïve rats and on potassium-evoked release of CGRP from sciatic nerves of naïve rats. Neither drug alone affected nociceptive behaviors or CGRP release. Two separate measures of mechanical nociceptive sensitivity remained unchanged after co-administration of the two drugs. In contrast, when deltorphin was co-injected with morphine, dose-dependent and peripherally-restricted increases in paw withdrawal latencies to radiant heat were observed. Similarly, concentration-dependent inhibition of CGRP release was observed when deltorphin and morphine were administered in sequence prior to potassium stimulation. However, no inhibition was observed when morphine was administered prior to deltorphin. All combined opioid effects were blocked by co-application of antagonists. Deltorphin exposure also enhanced the in vivo and in vitro effects of another μ-opioid receptor agonist, DAMGO. Together, these results suggest that under normal conditions, δ-opioid receptor agonists enhance the effect of μ-opioid receptor agonists in the periphery, and local co-administration of δ- and μ-opioid receptor agonists may improve results of peripheral opioid therapy for the treatment of pain.
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