Department of Neuroscience and Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN, USA.
Pain. 2010 Dec;151(3):763-770. doi: 10.1016/j.pain.2010.09.009.
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.
在动物模型中，组织损伤或炎症后外周阿片类药物镇痛作用增强已有充分的文献记载，但外周阿片类药物治疗的临床结果仍不一致。中枢神经系统的先前研究表明，μ 和 δ 阿片受体激动剂的共同给药可以增强镇痛效果；然而，关于在外周阿片受体相互作用的功能后果知之甚少。本研究检查了单独和组合足底注射 μ 和 δ 阿片受体激动剂吗啡和德尔塔啡对新生大鼠伤害感受行为测试和新生大鼠坐骨神经钾诱发 CGRP 释放的影响。两种药物单独使用均不影响伤害感受行为或 CGRP 释放。两种药物共同给药后，两种单独的机械性痛觉敏感性测量仍未改变。相比之下，当德尔塔啡与吗啡共同注射时，观察到对辐射热的足底撤回潜伏期呈剂量依赖性和外周受限增加。同样，当德尔塔啡和吗啡在钾刺激前顺序给药时，观察到 CGRP 释放的浓度依赖性抑制。然而，当吗啡先于德尔塔啡给药时，未观察到抑制作用。所有联合阿片类药物作用均被拮抗剂共同应用阻断。德尔塔啡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，在正常情况下，δ 阿片受体激动剂在外周增强 μ 阿片受体激动剂的作用，局部共同给予 δ 和 μ 阿片受体激动剂可能改善外周阿片类药物治疗疼痛的效果。
