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[每周一问]NO.20-Alpha 2 Adrenoceptor Agonists
1.  What are the analgesic effects of alpha 2 agonists?
2.  How do alpha 2 agonists provide analgesic effects?
1.α-2受体激动剂的镇痛作用是什么？
2.α-2受体激动剂如何发挥镇痛？

1.  α-2受体激动剂的镇痛效果是什么？
当给与系统口服，或通过中心轴索阻滞，α-2受体激动剂可以减轻术后和慢性疼痛[1]。虽然大剂量（如700-900μg可乐定）在硬膜外使用，显著的副作用包括低血压、心动过缓和出现镇静[2]。因此，推荐使用小剂量α-2受体激动剂复合其他药物；可乐定（150μg）合并芬太尼、吗啡和布比卡因已明确有增加术后镇痛持续时间的作用[3]。小剂量阿片类药物和α-2受体激动剂合用的结果是可带来更大程度的镇痛，而各自的副作用降低。因为有延续镇痛的很多证据，因此α-2受体激动剂被推荐作为癌症疼痛的治疗方法的一部分[4]。
2.α-2受体激动剂如何发挥镇痛？
一个机制包括可增强传统阿片类解热镇痛药的作用。临床显示α-2受体激动剂存在少量吗啡样作用[3]。动物试验的几项研究更精确的证明了这种关系。例如，Sanchez-Blazquez等[5]评估了α-2受体激动剂（咪唑啉复合物）在调节吗啡镇痛方面的作用。通过脑室内（i.c.v.）或皮下（s.c.）给与选择性或非选择性Ⅰ(2)-咪唑啉受体结合剂（2-BFI, LSL 60101, LSL 61122和阿胍诺定），作者得出：α-2受体激动剂可增加吗啡剂量依赖性产生的抗伤害性刺激作用。因此他们认为在α-2受体激动剂（Ⅰ(2)-咪唑啉）和阿片受体之间存在功能上的相关。
近期有证据表明α-2肾上腺素受体亚型的不同是鞘内给与α-2受体激动剂产生抗伤害性作用的原因。Graham等[6]提出了该观点的药理学证据，如同两个常用的斯普拉-道来(氏)大鼠杂交次代系受体功能的差异一样。通过使用等幅射分析，作者假设，如果鞘内给与α-2受体激动剂（ST-91和右旋美托咪啶）作为相同受体的激动剂，那么其作用应该相加。然而，如果证明存在超过相加的作用，则必然存在α-2肾上腺素受体的不同亚型。
通过用尾试验，作者观察到，当1：3的右旋美托咪啶和ST-91混合物用于Harlan和Sasco斯普拉-道来(氏)大鼠时，理论上的剂量-相加曲线明显左移。相似的剂量反应也在hot-plate试验中得到，虽然激动剂的剂量-反应特性在该试验中不同。在Harlan大鼠，ST-91匙完全激动剂，右旋美托咪啶和ST-91混合物的剂量-效应关系远离到剂量-相加曲线的左侧。相似的是，在Sasco大鼠，ST-91位部分激动剂，右旋美托咪啶无活性，同时服用这两种激动剂也使剂量反应关系移到剂量相加曲线的左侧。一致的发现是，这两种α-2受体激动剂作用效果超过相加提供了有力的证据：右旋美托咪啶和ST-91在脊髓通过作用于不同α-2受体亚型而发挥抗伤害性作用。作者认为其发现与早期的假设相一致，即右旋美托咪啶主要作用于α-（2A）肾上腺素受体，而ST-91主要作用于非α-（2A）肾上腺素受体（最可能α-（2C）亚型）。作者得出结论，α-（2A）和α-（2C）肾上腺素受体激动剂的协同作用可提供更有效的药物复合镇痛作用，而副作用相对于单一α-2受体激动剂达到相同镇痛作用时降低。
What are the analgesic effects of alpha 2 agonists?
When utilized orally, systemically, or through central neuraxial blockade, alpha 2 agonists have been noted to alleviate postoperative and chronic pain (1). Although larger doses (e.g. 700-900 µg clonidine) have been utilized epidurally, a significant incidence of side effects including hypotension, bradycardia, and sedation occur (2). As a consequence, smaller doses of alpha 2 agonists in combination with other medications has been advocated; clonidine (150 µg) with fentanyl, morphine, and bupivacaine has been noted to increase the duration of postoperative analgesia (3). The resulting combination of smaller doses of opioids and alpha 2 agonists has allowed the benefit of greater analgesia with reduced side effects of both medications. Due to the evidence accumulating regarding supplemental analgesia, alpha 2 agonists have been advocated as part of treatment algorithms for cancer pain (4).
How do alpha 2 agonists provide analgesic effects?
One mechanism appears to involve accentuation of the effects of traditional opioid pain relievers. Clinically, it appears that alpha 2 agonists exhibit a morphine-sparing effect (3). Several studies in animals have more precisely characterized this interaction. For example, Sanchez-Blazquez et al.(5) evaluated the action of alpha 2 agonists (imidazoline compounds) on the modulation of morphine analgesia. Through the intracerebroventricular (i.c.v.) or subcutaneous (s.c.) administration of selective and non-selective ligands for the I(2)-imidazoline receptor (2-BFI, LSL 60101, LSL 61122 and aganodine), the authors determined that alpha 2 agonists increase morphine-induced antinociception in a dose-dependent manner. The authors concluded that a functional interaction between alpha 2 agonists (I(2)-imidazoline) and opioid receptors existed.
Recent evidence suggests that different subtypes of alpha 2 adrenoceptors are responsible for the antinociception produced by the intrathecal administration of these agonists. Graham et al.  provided pharmacologic evidence for this idea, as well as for differences in the receptor function of two popular outbred substrains of Sprague-Dawley rats. By using isobolographic analysis, the authors hypothesized that if intrathecally administered alpha 2 agonists (ST-91 and dexmedetomidine) act as agonists at the same receptor, then their interaction should be additive. However, if a supra-additive interaction is demonstrated, different subtypes of alpha 2 adrenoceptors must exist .
Using the tail-flick test, the authors noted a significant left shift in the theoretical dose-additive line when a 1:3 mixture of dexmedetomidine and ST-91 was evaluated in both the Harlan and Sasco Sprague-Dawley rats. A similar dose response was made with the hot-plate test despite the fact that the dose-response characteristics of the agonists were different in this test. In Harlan rats, in which ST-91 is a full agonist, the dose-effect relationship for the mixture of dexmedetomidine and ST-91 was shifted far to the left of the dose-additive line. Similarly, in Sasco rats, in which ST-91 is a partial agonist and dexmedetomidine is inactive, co-administration of the two agonists also shifted the dose-response relationship to the left of the dose-additive line. The consistent finding that these two alpha 2 agonists interacted in a supra-additive manner provides strong evidence that dexmedetomidine and ST-91 produce antinociception by acting at different alpha 2 adrenoceptor subtypes in the spinal cord. The authors suggested that their findings were consistent with an earlier proposal that dexmedetomidine acts predominantly at alpha(2A)-adrenoceptors whereas ST-91 acts predominantly at non-alpha(2A)-adrenoceptors (most likely alpha(2C) type). The authors concluded that the synergistic combination of alpha(2A)- and alpha(2C)-adrenoceptor agonists may provide a more effective drug combination for the treatment of pain with less side effects than an equianalgesic dose of a single alpha 2 agonist.
References:
1.  Tejwani GA, Rattan AK. Antagonism of antinociception produced by intrathecal clonidine by ketorolac in the rat: the role of the opioid system. Anesth Analg 2000;90(5):1152-6.
2.  DeBels D, Coriat P. Alpha 2 adrenoceptor agonists: An increasing role in modern anesthesia. Problems in Anesthesia 2000;12:65-72.
3.  Eisenach JC, De Kock M, Klimscha W. alpha (2)-adrenergic agonists for regional anesthesia. A clinical review of clonidine (1984-1995). Anesthesiology 1996;85(3):655-74.
4.  Miguel R. Interventional treatment of cancer pain: the fourth step in the World Health Organization analgesic ladder? Cancer Control 2000;7(2):149-56.
5.  Sanchez-Blazquez P, Boronat MA, Olmos G et al. Activation of I(2)-imidazoline receptors enhances supraspinal morphine analgesia in mice: a model to detect agonist and antagonist activities at these receptors. Br J Pharmacol 2000 May;130(1):146-52.
6.  Graham BA, Hammond DL, Proudfit HK. Synergistic interactions between two alpha(2)-adrenoceptor agonists, dexmedetomidine and ST-91, in two substrains of Sprague-Dawley rats. Pain 2000 Mar;85(1-2):135-43.
Site Editor: Stephen B. Corn, M.D. and B. Scott Segal, M.D.
Department of Anesthesia, Harvard Medical School
Founders and Editors-in-Chief: Stephen B. Corn, M.D. and B. Scott Segal, M.D.
Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Medical School