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 delivery. The current work characterizes the dose-dependent antinociception and effects upon respiratory function of dexmedetomidine after intrathecal, epidural, intravenous, and intracisternal delivery in chronically prepared dogs.


METHODS
Dogs were prepared with chronic tracheostomies and trained to perform rebreathing studies. These animals were then prepared with chronic lumbar intrathecal, epidural, or intracisternal catheters.


RESULTS
A rapid dose-dependent increase in the thermal skin twitch response latency and paw withdrawal to mechanical pinch was observed after intrathecal, epidural, and intravenous dexmedetomidine (dose required to reach 50% of maximal effect for skin twitch = 1.8, 10, and 15 micrograms, respectively) but not after intracisternal dexmedetomidine (> 15 microgram), with the maximally effective dose lasting approximately 90 min. The spinal effect was unaccompanied by effects upon behavioral alertness, motor function, or changes in CO2 response. In contrast, intravenous dexmedetomidine (1-10 micrograms/kg) resulted in a dose-dependent sedation and a significant reduction in heart rate and respiratory rate and a diminished response to increased CO2, these effects lasting approximately 2 h. Intracisternal administration of up to 15 micrograms had no effect upon the nociceptive threshold, and CO2 response, and failed to result in a significant reduction in alertness. All of the effects of dexmedetomidine were antagonized by the alpha 2-antagonist atipamezole (30-300 micrograms/kg, intravenous), but not by the opioid antagonist naloxone (30 micrograms/kg, intravenous), while atipamezole did not reverse the antinociceptive or respiratory depressant actions of intravenous sufentanil (50 micrograms), effects which were reversible by naloxone.


CONCLUSIONS
Dexmedetomidine, acting through an alpha 2-receptor, produces a powerful antinociceptive effect, mediated at the spinal level, while systemic redistribution of the drug leads to a hypnotic state with significant cardiorespiratory effects.
Sabbe
M B
MB
Department of Emergency Medicine, Catholic University of Leuven, Belgium.
Penning
J P
JP
Ozaki
G T
GT
Yaksh
T L
TL
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000767:Anesthesia, Epidural; D000775:Anesthesia, Spinal; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002245:Carbon Dioxide / Q000032:analysis*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005552:Forelimb; D006339:Heart Rate / Q000187:drug effects*; D006614:Hindlimb; D007093:Imidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D007262:Infusions, Intravenous; D007263:Infusions, Parenteral; D020926:Medetomidine; D009043:Motor Activity / Q000187:drug effects; D009270:Naloxone / Q000494:pharmacology; D010146:Pain; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology*; D012119:Respiration / Q000187:drug effects*
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D007093:Imidazoles; D018341:Receptors, Adrenergic, alpha-2; C050701:atipamezole; D002245:Carbon Dioxide; D009270:Naloxone; D020926:Medetomidine