Graham B A, Hammond D L, Proudfit H K
Department of Anesthesia and Critical Care, University of Chicago, 5841 South Maryland Avenue M/C4028, Chicago, USA.
Pain. 2000 Mar;85(1-2):135-43. doi: 10.1016/s0304-3959(99)00261-4.
Several lines of evidence indicate that the antinociception produced by intrathecal administration of the alpha(2)-adrenoceptor agonists dexmedetomidine or ST-91 is mediated by different subtypes of the alpha(2)-adrenoceptor. We recently provided additional pharmacologic evidence for this idea, as well as for differences in the function of these receptors between Harlan and Sasco rats, two widely-used outbred substrains of Sprague-Dawley rat. The present study used isobolographic analysis to further characterize the receptors at which intrathecally administered ST-91 and dexmedetomidine act in these two substrains. The rationale for these studies derives from the assumption that if dexmedetomidine and ST-91 act as agonists at the same receptor then they should interact in an additive manner. However, if they interact in a supra-additive manner, then they must act at different subtypes of the alpha(2)-adrenoceptor. In the tail-flick test, the dose-effect relationship for a 1:3 mixture of dexmedetomidine and ST-91 was shifted significantly to the left of the theoretical dose-additive line in both Harlan and Sasco Sprague-Dawley rats. A similar finding was made in the hot-plate test despite the fact that the dose-response characteristics of the agonists were different in this test. Thus, in Harlan rats, in which ST-91 is a full agonist and dexmedetomidine is essentially inactive, 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)-adrenoceptor agonists interact 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. This conclusion is consistent with the earlier proposal that dexmedetomidine acts predominantly at alpha(2A)-adrenoceptors whereas ST-91 acts predominantly at non-alpha(2A)-adrenoceptors. Recent anatomical evidence indicates that these non-alpha(2A) adrenoceptors may be of the alpha(2C) type. The synergistic combination of an alpha(2A)- and an alpha(2C)-adrenoceptor agonist may provide a unique and highly effective drug combination for the treatment of pain without the sedation produced by an equianalgesic dose of a single alpha(2)-adrenoceptor agonist.
多条证据表明，鞘内注射α₂-肾上腺素能受体激动剂右美托咪定或ST-91所产生的镇痛作用是由不同亚型的α₂-肾上腺素能受体介导的。我们最近为这一观点提供了更多药理学证据，同时也证明了在两种广泛使用的远交系Sprague-Dawley大鼠亚系（Harlan大鼠和Sasco大鼠）中，这些受体的功能存在差异。本研究采用等效应线分析法，进一步明确鞘内注射的ST-91和右美托咪定在这两个亚系中所作用的受体。这些研究的理论依据基于这样的假设：如果右美托咪定和ST-91作用于同一受体的激动剂，那么它们应该以相加的方式相互作用。然而，如果它们以超相加的方式相互作用，那么它们必定作用于不同亚型的α₂-肾上腺素能受体。在甩尾试验中，右美托咪定和ST-91 1:3混合物的剂量-效应关系在Harlan大鼠和Sasco Sprague-Dawley大鼠中均显著向左偏移至理论剂量相加线的左侧。在热板试验中也得到了类似的结果，尽管在该试验中激动剂的剂量-反应特性有所不同。因此，在ST-91是完全激动剂而右美托咪定基本无活性的Harlan大鼠中，右美托咪定和ST-91混合物的剂量-效应关系远远向左偏移至剂量相加线的左侧。同样，在ST-91是部分激动剂而右美托咪定无活性的Sasco大鼠中，两种激动剂联合给药也使剂量-反应关系向左偏移至剂量相加线的左侧。这两种α₂-肾上腺素能受体激动剂始终以超相加方式相互作用这一发现，有力地证明了右美托咪定和ST-91通过作用于脊髓中不同的α₂-肾上腺素能受体亚型产生镇痛作用。这一结论与早期的观点一致，即右美托咪定主要作用于α₂A-肾上腺素能受体，而ST-91主要作用于非α₂A-肾上腺素能受体。最近的解剖学证据表明，这些非α₂A-肾上腺素能受体可能是α₂C型。α₂A-和α₂C-肾上腺素能受体激动剂的协同组合可能为疼痛治疗提供一种独特且高效的药物组合，而不会产生等效镇痛剂量的单一α₂-肾上腺素能受体激动剂所引起的镇静作用。
