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We continue our discussion of the most commonly used analgesics in the management of pain, opioids.
1.  What are the endogenous peptides in humans that bind to opioid receptors?
2.  Where are opioid receptors primarily located?
3.  How does opioid receptor binding lead to pain relief?
我们继续讨论阿片药物
1．  在人体作用于阿片受体的内源性肽是什么？
2．  阿片受体主要位于哪儿？
3．  阿片受体是如何减轻疼痛的？

[每周一问]No.2之周中问：最常用的镇痛药物—阿片样物质

在人体作用于阿片受体的内源性肽是什么？
现在已知的有三种主要的内源性阿片类受体因子：脑啡肽、内啡肽、强啡肽

阿片受体主要位于哪儿？
阿片受体主要位于脑和脊髓。近期研究表明阿片受体在外周的作用增加，特别是在炎性部位。（以后还将进行外周阿片受体的讨论）。
在大脑，在脑干导水管周围灰质区、杏仁核、the corpus stritaum（松果体？）和下丘脑区阿片受体浓度很高。在脊髓Substantia Gelatinosa (Rexed Laminae II)区阿片受体浓度很高。最近关于镇痛的研究理论支持内啡肽或阿片物质结合于疼痛感觉的特殊区域。
所有的阿片受体(mu, kappa, and delta)都是G-蛋白并有7次跨膜区域，其结合通常导致细胞活性降低。

阿片受体结合是如何减轻疼痛的？
阿片受体位于突触前或突触后。突触前结合阿片制剂可以抑制钙通道，激火内部的钾泵，或抑制腺苷酸环化酶的生成。这三种作用减少神经递质的释放，使神经超级化，最后导致神经细胞冲动的减少。
阿片物质可能直接抑制突触后神经递质的结合。如下是脊髓背侧角的阿片物质可能作用的例子：

图一：阿片物质或内啡肽潜在疼痛调节区域。阿片物质调节升高和降低神经传导通路。
thalamus丘脑central gray中央灰质brainstem脑干spinothalamic脊髓丘脑的dorsal horn背侧角spinal cord脊髓nociceptor伤害性感受器
 

图二：阿片物质的结合部位与作用机理。
 

What are the endogenous peptides in humans that bind to opioid receptors?
The three main endogenous opioid receptor agents are known as:
•  enkephalins
•  endorphins
•  dynorphins

Where are opioid receptors primarily located?
Opioid Receptors are primarily located in the brain and spinal cord. Recent evidence points to the increasing role of opioid receptors in the periphery, especially in inflammatory states. (For a discussion of peripheral opioid receptors, see questions later in this syllabus topic).
In the brain, there is a high concentration of opioid receptors in the brainstem periaquaduetal gray area, the amygdala, the corpus stritaum and the hypothalamus. In the spinal cord there is a high concentration of opioid receptors in the Substantia Gelatinosa (Rexed Laminae II). The most recent theories of analgesia support the concept that endorphins, or opioids, bind to receptors in specific areas of pain perception.
All the opioid receptors (mu, kappa, and delta) are G-protein linked and have 7 transmembrane spanning regions that when bound usually lead to decreased cell activity.

How does opioid receptor binding lead to pain relief?
Opioid receptors can be located presynaptically or postsynaptically. Presynaptically bound opiates may inhibit Ca2+ channels, activate inwardly directed K+ pumps, or inhibit the production of adenyl cyclase. These three actions lead to decreased neurotransmitter release, hyperpolarization of the nerve, and ultimately a decreased chance of the nerve cell firing.
Opioids probably directly inhibit the binding of neurotransmitters postsynaptically. An example of possible opioid interaction in the dorsal horn of the spinal cord is displayed below:

Figure 1: Areas of potential modulation of pain by opioids or endorphins. Opioids modulate both ascending and descending nerve transmission pathways.
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Figure 2: Binding sites and mechanism of action of opioids
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References:
1.  Satoh M, Minami M. Molecular Pharmacology of the opioid receptor. Pharmacol Ther 68:343-65, 1995.
2.  Yaksh TL. Spinal Opiate Analgesia: Characteristics and principles of Action Pain II 11:293-346, 1981.
Site Editor: Sunil Eappen, M.D.
Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Medical School