SPINAL AND SYSTEMIC ACTION OF THE ALPHA(2) RECEPTOR AGONIST DEXMEDETOMIDINE IN DOGS - ANTINOCICEPTION AND CARBON-DIOXIDE RESPONSE

Background: alpha(2) Agonists are powerful analgesics after spinal del ivery. The current work characterizes the dose-dependent antinocicepti on and effects upon respiratory function of dexmedetomidine after intr athecal, epidural, intravenous, and intracisternal delivery in chronic ally prepared dogs. Methods: Dogs were prepared with chronic tracheost omies and trained to perform rebreathing studies. These animals were t hen prepared with chronic lumbar intrathecal, epidural, or intracister nal catheters. Results: A rapid dose-dependent increase in the thermal skin twitch response latency and paw withdrawal to mechanical pinch w as observed after intrathecal, epidural, and intravenous dexmedetomidi ne (dose required to reach 50% of maximal effect for skin twitch = 1.8 , 10, and 15 mu g, respectively) but not after intracisternal dexmedet omidine (>15 mu g), with the maximally effective dose lasting approxim ately 90 min. The spinal effect was unaccompanied by effects upon beha vioral alertness, motor function, or changes in CO, response. In contr ast, intravenous dexmedetomidine (1-10 mu g/kg) resulted in a dose-dep endent sedation and a significant reduction in heart rate and respirat ory rate and a diminished response to increased CO2, these effects las ting approximately 2 h. Intracisternal administration of up to 15 mu g had no effect upon the nociceptive threshold, and CO2 response, and f ailed to result in a significant reduction in alertness. All of the ef fects of dexmedetomidine were antagonized by the alpha(2)-antagonist a tipamezole (30-300 mu g/kg, intravenous), but not by the opioid antago nist naloxone (30 mu g/kg, intravenous), while atipamezole did not rev erse the antinociceptive or respiratory depressant actions of intraven ous sufentanil (50 mu g), effects which were reversible by naloxone. C onclusions: Dexmedetomidine, acting through an alpha(2)-receptor, prod uces a powerful antinociceptive effect, mediated at the spinal level, while systemic redistribution of the drug leads to a hypnotic state wi th significant cardiorespiratory effects.