Synergistic interactions between two alpha(2)-adrenoceptor agonists, dexmedetomidine and ST-91, in two substrains of Sprague-Dawley rats

Several lines of evidence indicate that the antinociception produced by int rathecal administration of the alpha(2)-adrenoceptor agonists dexmedetomidi ne or ST-91 is mediated by different subtypes of the alpha(2)-adrenoceptor. We recently provided additional pharmacologic evidence for this idea, as w ell as for differences in the function of these receptors between Harlan an d Sasco rats, two widely-used outbred substrains of Sprague-Dawley rat. The present study used isobolographic analysis to further characterize the rec eptors at which intrathecally administered ST-91 and dexmedetomidine act in these two substrains. The rationale for these studies derives from the ass umption that if dexmedetomidine and ST-91 act as agonists at the same recep tor then they should interact in an additive manner. However, if they inter act in a supra-additive manner, then they must act at different subtypes of the alpha(2)-adrenoceptor. In the tail-hick test, the dose-effect relation ship for a 1:3 mixture of dexmedetomidine and ST-91 was shifted significant ly to the left of the theoretical dose-additive line in both Harlan and Sas co Sprague-Dawley rats. A similar finding was made in the hot-plate test de spite 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 agon ist and dexmedetomidine is essentially inactive, the dose-effect relationsh ip 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 p artial agonist and dexmedetomidine is inactive, co-administration of the tw o agonists also shifted the dose-response relationship to the left of the d ose-additive line. The consistent finding that these two alpha(2)-adrenocep tor agonists interact in a supraadditive manner provides strong evidence th at dexmedetomidine and ST-91 produce antinociception by acting at different alpha(2)-adrenoceptor subtypes in the spinal cord. This conclusion is cons istent 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 ale type. The synergistic combination of an a lpha(2A)- and an alpha(2C)-adrenoceptor agonist may provide a unique and hi ghly effective drug combination for the treatment of pain without the sedat ion produced by an equianalgesic dose of a single alpha(2)-adrenoceptor ago nist. (C) 2000 International Association for the Study of Pain. Published b y Elsevier Science B.V. All rights reserved.