ArticlesSynergistic interactions between twoα2-adrenoceptor agonists, dexmedetomidine and ST-91, in two substrains of Sprague–Dawley ratsGraham, Brent Aa; Hammond, Donna La; Proudfit, Herbert Kb,*Author Information aDepartment of Anesthesia and Critical Care, University of Chicago, 5841 South Maryland Avenue M/C4028, Chicago, IL 60637, USA bDepartment of Pharmacology (mc868), University of Illinois at Chicago, 835 South Wolcott Avenue, Chicago, IL 60612, USA * Corresponding author. Tel.: +1-312-996-2349; fax: +1-312-996-1225 E-mail address:[email protected] Received 20 May 1999; received in revised form 28 September 1999; accepted 29 October 1999. Pain: March 1, 2000 - Volume 85 - Issue 1 - p 135-143 doi: 10.1016/S0304-3959(99)00261-4 Buy Metrics Abstract Several lines of evidence indicate that the antinociception produced by intrathecal administration of the α2-adrenoceptor agonists dexmedetomidine or ST-91 is mediated by different subtypes of the α2-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 α2-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 α2-adrenoceptor agonists interact in a supra-additive manner provides strong evidence that dexmedetomidine and ST-91 produce antinociception by acting at different α2-adrenoceptor subtypes in the spinal cord. This conclusion is consistent with the earlier proposal that dexmedetomidine acts predominantly at α2A-adrenoceptors whereas ST-91 acts predominantly at non-α2A-adrenoceptors. Recent anatomical evidence indicates that these non-alpha2A adrenoceptors may be of the α2C type. The synergistic combination of an α2A- and an α2C-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 α2-adrenoceptor agonist. © 2000 Lippincott Williams & Wilkins, Inc.