ANTINOCICEPTIVE ACTIONS OF DEXMEDETOMIDINE AND THE KAPPA-OPIOID AGONIST U-50,488H AGAINST NOXIOUS THERMAL, MECHANICAL AND INFLAMMATORY STIMULI

The antinociceptive efficacies of both intrathecally (i.t.) and system ically administered dexmedetomidine (a selective alpha-2 adrenoceptor agonist) and U-50,488H [trans(+/-)-3,4-dichloro-N-methyl-N-[2-(1 -pyrr olidinyl)-cyclohexyl]-benzene-acetamide] (a kappa-opioid receptor agon ist) were studied during peripheral inflammation induced by carrageena n. The antinociceptive tests were the hot plate (HP), the tail flick ( TF) and the paw pressure tests (PP). The motor incoordination, if any, produced by both i.t. and s.c. dexmedetomidine were evaluated with th e rotarod. The interaction between dexmedetomidine and U-50,488H and b etween atipamezole (a selective alpha-2 adrenoceptor antagonist) and U -50,488H were also assessed. The carrageenan injection induced not onl y peripheral hyperalgesia but also central sensitization, as assessed by decreased PP and TF latencies, respectively. The i.t. dexmedetomidi ne (0.15, 0.45, 1.35, 4.05) mu g) resulted in dose-dependent increases in the PP thresholds and TF latencies in both the control rats and th e rats with unilateral inflammation, without causing changes in motor coordination, whereas on s.c. administration of dexmedetomidine (3-100 mu g/kg), antinociception was produced in PP only at doses (30 mu g/k g) that already interfered with rotarod performance. U-50,488H was ine ffective i.t. (5-200 mu g) but, on s.c. administration (2.5-22.5 mg/kg ), dose-dependent increases were found in the PP thresholds and TF lat encies of the rats with unilateral inflammation. Atipamezole, in a dos e (3 mg/kg) that has been shown to block the antinociceptive effects o f dexmedetomidine, did not modify the antinociceptive effects of U-50, 488H. Coadministration of dexmedetomidine (0.45 mu g i.t.) with U-50,4 88H (2.5 mg/kg s.c.) resulted in additive effects in the PP test on bo th paws and in the TF test in the inflamed-paw rats. Dexmedetomidine a nd U-50,488H produced antinociception in the rats with inflammation at doses devoid of any antinociceptive effect in control rats. This sugg ests an enhanced antinociceptive effect for both dexmedetomidine and U -50,488H during peripheral inflammation and the consequent central sen sitization. Thermal tests seem to be more sensitive to detect this eff ect.