Stein Christoph, Zöllner Christian
Klinik für Anaesthesiologie und operative Intensivmedizin, Freie Universität Berlin, Charité - Campus Benjamin Franklin, 12200 Berlin, Germany.
Handb Exp Pharmacol. 2009(194):495-518. doi: 10.1007/978-3-540-79090-7_14.
This chapter reviews the expression and regulation of opioid receptors in sensory neurons and the interactions of these receptors with endogenous and exogenous opioid ligands. Inflammation of peripheral tissues leads to increased synthesis and axonal transport of opioid receptors in dorsal root ganglion neurons. This results in opioid receptor upregulation and enhanced G protein coupling at peripheral sensory nerve terminals. These events are dependent on neuronal electrical activity, and on production of proinflammatory cytokines and nerve growth factor within the inflamed tissue. Together with the disruption of the perineurial barrier, these factors lead to an enhanced analgesic efficacy of peripherally active opioids. The major local source of endogenous opioid ligands (e.g. beta-endorphin) is leukocytes. These cells contain and upregulate signal-sequence-encoding messenger RNA of the beta-endorphin precursor proopiomelanocortin and the entire enzymatic machinery necessary for its processing into the functionally active peptide. Opioid-containing immune cells extravasate using adhesion molecules and chemokines to accumulate in inflamed tissues. Upon stressful stimuli or in response to releasing agents such as corticotropin-releasing factor, cytokines, chemokines, and catecholamines, leukocytes secrete opioids. Depending on the cell type, this release is contingent on extracellular Ca(2+) or on inositol triphosphate receptor triggered release of Ca(2+) from endoplasmic reticulum. Once secreted, opioid peptides activate peripheral opioid receptors and produce analgesia by inhibiting the excitability of sensory nerves and/or the release of proinflammatory neuropeptides. These effects occur without central untoward side effects such as depression of breathing, clouding of consciousness, or addiction. Future aims include the development of peripherally restricted opioid agonists, selective targeting of opioid-containing leukocytes to sites of painful injury, and the augmentation of peripheral opioid peptide and receptor synthesis.
本章回顾了阿片受体在感觉神经元中的表达与调控，以及这些受体与内源性和外源性阿片配体的相互作用。外周组织炎症导致背根神经节神经元中阿片受体的合成增加和轴突运输增强。这导致外周感觉神经末梢处阿片受体上调以及G蛋白偶联增强。这些事件依赖于神经元电活动以及炎症组织中促炎细胞因子和神经生长因子的产生。连同神经束膜屏障的破坏，这些因素导致外周活性阿片类药物的镇痛效果增强。内源性阿片配体（如β-内啡肽）的主要局部来源是白细胞。这些细胞含有并上调β-内啡肽前体阿黑皮素原的信号序列编码信使核糖核酸以及将其加工成功能活性肽所需的整个酶促机制。含阿片类药物的免疫细胞利用黏附分子和趋化因子渗出，聚集在炎症组织中。在应激刺激下或响应释放剂（如促肾上腺皮质激素释放因子、细胞因子、趋化因子和儿茶酚胺）时，白细胞分泌阿片类药物。根据细胞类型的不同，这种释放取决于细胞外钙离子或肌醇三磷酸受体触发的内质网钙离子释放。一旦分泌，阿片肽就会激活外周阿片受体，并通过抑制感觉神经的兴奋性和/或促炎神经肽的释放来产生镇痛作用。这些作用不会产生诸如呼吸抑制、意识模糊或成瘾等中枢不良反应。未来的目标包括开发外周受限的阿片激动剂、将含阿片类药物的白细胞选择性靶向疼痛损伤部位，以及增强外周阿片肽和受体的合成。
