Vadivelu Nalini, Mitra Sukanya, Hines Roberta L
Department of Anesthesiology, Yale University School of Medicine, New Haven, Connecticut, USA.
J Opioid Manag. 2011 Jan-Feb;7(1):55-68. doi: 10.5055/jom.2011.0049.
It is established that opioid receptors are present in the dorsal root ganglia and the central as well as peripheral terminals ofprimary afferent neurons. Now, it has been shown that peripheral terminals of afferent nerves can be the sites of the intrinsic modulation of nociception and that opioid analgesia can be mediated by peripheral opioid receptors as well.
This review focuses on two areas: the first on describing the peripheral opioidergic system, and the second on the review of the current state of development of peripherally active opioid receptor agonists with theirpotential clinical applications.
Online and manual search using key words such as peripheral opioid receptors, peripheral (or peripherally restricted) opioid agonists, and peripheral mu-, kappa-, and delta-opioid receptor agonists, followed by full-text access and further cross-referencing.
The obvious theoretical advantage of using these molecules is that analgesia is achieved while avoiding the bothersome-to-dangerous centrally mediated adverse effects of centrally acting opioids. Molecules knownum for their central action (e.g.,, morphine) have been used in peripheral tissues (joints, bone, teeth) with reasonable but varied success. Over the last 10-15 years, several molecules with peripherally restricted opioid agonist activity have been developed and several more are in the "clinical pipeline. "Although none is available as an approved medication till date, a few (e.g.; the peripherally restricted kappa-agonist FE200665, also known as CR665) have completed phase I clinical trials and currently in phase II. Others such as loperamide, which is approved for use as an antidiarrheal drug, have been found to be variably useful as a peripherally acting opioid analgesic.
Substantive research is currently underway and this is an exciting research area for both basic and applied clinical fields. Various ways to enhance peripheral opioid analgesia are suggested.
已证实阿片受体存在于背根神经节以及初级传入神经元的中枢和外周终末。现在，已经表明传入神经的外周终末可以是伤害感受内在调节的部位，并且阿片类镇痛也可以由外周阿片受体介导。
本综述聚焦于两个领域：第一个是描述外周阿片能系统，第二个是综述外周活性阿片受体激动剂的当前发展状况及其潜在临床应用。
使用外周阿片受体、外周（或外周限制型）阿片激动剂以及外周μ、κ和δ阿片受体激动剂等关键词进行在线和手动搜索，随后获取全文并进一步交叉引用。
使用这些分子的明显理论优势在于，在实现镇痛的同时避免了中枢作用阿片类药物令人烦恼甚至危险的中枢介导的不良反应。一些已知具有中枢作用的分子（例如吗啡）已用于外周组织（关节、骨骼、牙齿），取得了一定但各不相同的成功。在过去10至15年中，已经开发出几种具有外周限制型阿片激动剂活性的分子，还有几种正在“临床试验阶段”。尽管迄今为止尚无一种作为获批药物上市，但有几种（例如外周限制型κ激动剂FE200665，也称为CR665）已完成I期临床试验，目前处于II期。其他一些药物，如被批准用作止泻药的洛哌丁胺，已被发现作为外周作用的阿片类镇痛药有不同程度的效用。
目前正在进行大量研究，这对基础和应用临床领域来说都是一个令人兴奋的研究领域。文中提出了增强外周阿片类镇痛的各种方法。
