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[每周一问]NO.21-Alpha 2 Adrenoceptor Agonists
1.  What are the anesthetic sparing effects of alpha 2 agonists?
2.  Where do these alpha 2 agonist anesthetic-sparing effects occur?
1.  α-2受体激动剂的轻度镇痛作用指的是什么？
2.  α-2受体激动剂的此类轻度镇痛作用的机理？

参考答案
1.α-2受体激动剂的轻度镇痛作用指的是什么？
α-2受体激动剂最初作为抗焦虑药和镇静药使用，当术前给予时，发现其可显著减少麻醉药的需要量[1，2]。主要是因为这些药物的镇静作用和血流动力学特性，其对麻醉剂需求减少的影响也可以通过药代动力学相互作用给与解释。Richards等[3]认为可乐定延长阿芬太尼的清除半衰期，使其血浆浓度增加60%。此外，当加入到局部麻醉如硬膜外、脊髓或外周阻滞时，局部麻醉的作用延长，效果增强[4]。Kita等[1]发现，在全麻吸入氟烷的大鼠，α-2受体激动剂可乐定可减少麻醉剂的需要量，并降低大鼠对伤害性刺激的血流动力学反应。当前的许多临床研究正在试图进一步研究这种现象。
有趣的是，所有抗伤害性刺激的药物疗法的这种增强治疗的相互作用尚未观察到。Tejwani等[4]证明，酮咯酸（痛力克）可抑制可乐定的抗伤害性刺激作用，当同时鞘内给予时。作为一种可能对这种现象的解释，Aley和Levine[5] 发现，μ阿片剂、α-2受体激动剂和A1腺苷受体激动剂也许需要所有三种激动剂的自然存在，以产生任何一激动剂的抗伤害性作用。因此他们提出了存在一个包含三种激动剂的复合物，在调节抗伤害性中发挥作用，至少在外周是这样的。NSAIDS如酮咯酸可能通过与该复合物或其他作用而调节伤害感觉。
2.α-2受体激动剂的此类轻度镇痛作用的机理？
随着α-2受体激动剂有益作用的逐渐发现，更多的研究主要集中在这些激动剂是如何以及在何处介导这些反应。争论主要存在于脊髓或神经索受体何者更重要上。Asano等[6]发现脊髓上存在这些受体。通过测量这些硬膜外α-2受体激动剂的作用位点、亲和力和相对抗伤害性能力，作者发现伤害性作用与脊髓α-2受体的亲和力直接成比例相关。然而，他们也认为，这些激动剂的心血管作用更可能是因为中枢神经系统内外的共同作用。Kita等[1]则确认α-2受体激动剂存在于神经索上的位点。通过测量与最小肺泡麻醉浓度（MAC）相关的中枢神经系统位点和MAC阻断肾上腺能反应（MAC-BAR），作者估计了在氟烷麻醉大鼠的全身给与可乐定的作用。氟烷的MAC通过夹尾试验决定，MAC-BAR则定义为在夹尾试验后血流动力学反应减弱10%以内的MAC。在α-育亨宾存在（一种α-2受体拮抗剂，通过静脉注射IV、鞘内给予IT、脑池内注射IC或脑室内注射ICV）时，给与可乐定静脉注射，发现可乐定可剂量依赖性减少MAC和MAC-BAR。α-育亨宾IV和ICV对抗可乐定的降低MAC作用，而α-育亨宾IC和IT则不能对抗。比较之下，α-育亨宾IV、ICV、IC可对抗可乐定的降低MAC-BAR作用；α-育亨宾IT则没有该效果。作者因此得出结论，α-2受体存在于中脑以上部位，而低位脑干则伴或不伴有对全身使用可乐定大鼠MAC和MAC-BAR的降低作用。相比较的是，脊髓α-2受体则没有这些显著的作用。
对α-2受体激动剂的进一步研究使得这些药物的作用位点和相互作用将越来越清晰。
What are the anesthetic sparing effects of alpha 2 agonists?
Initially utilized for their anxiolytic and sedative properties, alpha 2 agonists, when given preoperatively, have been noted to significantly decrease anesthetic requirements (1, 2). Primarily attributed to both the sedative and hemodynamic properties of these agents, this decrease in requirements may also be explained through pharmacokinetic interactions. Richards et al. (3) noted that clonidine prolonged the elimination half life of alfentanil, yielding a 60% increase in plasma levels. Moreover, when added to local anesthetics for epidural, spinal, or peripheral blockade, the resulting regional anesthetic is prolonged and intensified (4). During the provision of general anesthesia, Kita et al. (1) demonstrated that the alpha 2 agonist clonidine, reduced the anesthetic requirements and attenuated hemodynamic responses to noxious stimuli in rats administered halothane. A number of clinical studies are currently in progress to further delineate this phenomenon.
Interestingly, enhanced therapeutic interactions with all antinociceptive medications has not been observed. Tejwani et al. (4) demonstrated that ketorolac inhibited the antinociceptive effects of clonidine when both were administered intrathecally. As a possible explanation for this observation, Aley and Levine (5) noted that µ opioids, alpha 2 agonists, and A1-adenosine agonists may require the physical presence of all three agonists to produce antinocieption by any one agonist. They proposed that a complex, involving these three agonists, was responsible for mediating antinociception, at least in the periphery. It is possible that NSAIDS, like ketorolac, may negatively interact with this or other complexes modulating nociception.
Where do these anesthetic sparing effects occur?
As beneficial effects of alpha 2 agonists continue to be demonstrated, additional work has focused on how and where these agonists mediate their responses. Controversy exists as to whether spinal or supraspinal receptors are more important. Asano et al.  make a convincing case for a spinal location of these receptors. By measuring the location, affinity, and the relative antinociceptive potencies of epidural alpha 2 agonists, the authors found that nociception was directly proportional to the binding affinity to spinal alpha 2-adrenoceptors. However, they also noted that the cardiovascular effects of these agonists most probably resulted from actions both inside and outside the central nervous system. Kita et al. (1) confirmed that supraspinal locations for the alpha 2 agonists exist. By examining the CNS sites of action associated with minimum alveolar anesthetic concentration (MAC) and MAC blocking adrenergic response (MAC-BAR),the authors evaluated the effects of systemically administered clonidine in halothane-anesthetized rats. The MAC for halothane was determined by the tail clamp method, and MAC-BAR was defined as the MAC which attenuated hemodynamic responses within 10% after the tail clamp. The effect of IV clonidine was investigated in the presence of rauwolscine, an alpha 2 antagonist, given through IV, intrathecal (IT), intracisternal (IC), or intracerebroventrical (ICV) routes. IV clonidine was observed to reduce MAC and MAC-BAR dose-dependently. IV and ICV rauwolscine antagonized the MAC-reducing effect of clonidine, whereas IC and IT rauwolscine did not. In comparison, IV, ICV, and IC rauwolscine antagonized the MAC-BAR-reducing effect of clonidine; IT rauwolscine had no effect. The authors concluded that the alpha 2 adrenoceptors in the regions above mesencephalon with and without the lower brainstem were responsible for the MAC-BAR and MAC reducing effects of systemic clonidine in rats, respectively. By contrast, the spinal alpha 2 adrenoceptors did not contribute significantly to these effects.
Further work with alpha 2 agonists will hopefully delineate the locations and interactions of these agents.
References:
1.  Kita T, Kagawa K, Mammoto T et al. Supraspinal, not spinal, alpha (2) adrenoceptors are involved in the anesthetic-sparing and hemodynamic-stabilizing effects of systemic clonidine in rats. Anesth Analg 2000;90(3):722-6.
2.  DeBels D, Coriat P. Alpha 2 adrenoceptor agonists: An increasing role in modern anesthesia. Problems in Anesthesia 2000;12:65-72.
3.  Richards MJ, Skues MA, Jarvis AP, et al. Total iv anaesthsia with propofol and alfentanil: dose requirements for propofol and the effect of premedication with clonidine. Br J Anaesth 1990;65:157-63.
4.  Tejwani GA, Rattan AK. Antagonism of antinociception produced by intrathecal clonidine by ketorlac in the rat: the role of the opioid system. Anesth Analg 2000;90:1152-6.
5.  Aley KO, Levine JD. Multiple receptors involved in peripheral alpha 2, mu, and A1 antinociception, tolerance, and withdrawal. J Neurosci 1997;17(2):735-44.
6.  Asano T, Dohi S, Ohta S, Shimonaka H, Iida H. Antinociception by epidural and systemic alpha(2)-adrenoceptor agonists and their binding affinity in rat spinal cord and brain. Anesth Analg 2000;90(2):400-7.
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