Antagonism of the antinocifensive action of halothane by intrathecal administration of GABAA receptor antagonists.
BACKGROUND
The hind brain and the spinal cord, regions that contain high concentrations of gamma-aminobutyric acid (GABA) and GABA receptors, have been implicated as sites of action of inhalational anesthetics. Previous studies have established that general anesthetics potentiate the effects of gamma-aminobutyric acid at the GABAA receptor. It was therefore hypothesized that the suppression of nocifensive movements during anesthesia is due to an enhancement of GABAA receptor-mediated transmission within the spinal cord.


METHODS
Rats in which an intrathecal catheter had been implanted 1 week earlier were anesthetized with halothane. Core temperature was maintained at a steady level. After MAC determination, the concentration of halothane was adjusted to that at which the rats last moved in response to tail clamping. Saline, a GABAA, a GABAB, or glycine receptor antagonist was then injected intrathecally. The latency to move in response to application of the tail clamp was redetermined 5 min later, after which the halothane concentration was increased by 0.2%. Response latencies to application of the noxious stimulus were measured at 7-min intervals during the subsequent 35 min. To determine whether these antagonists altered baseline response latencies by themselves, another experiment was conducted in which the concentration of halothane was not increased after intrathecal administration of GABAA receptor antagonists.


RESULTS
Intrathecal administration of the GABAA receptor antagonists bicuculline (0.3 micrograms) or picrotoxin (0.3, 1.0 micrograms) antagonized the suppression of nocifensive movement produced by the small increase in halothane concentration. In contrast, the antinocifensive effect of the increase in halothane concentration was not attenuated by the GABAB receptor antagonist CGP 35348 or the glycine receptor antagonist strychnine. By themselves, the GABAA receptor antagonists did not alter response latency in rats anesthetized with sub-MAC concentrations of halothane.


CONCLUSIONS
Intrathecal administration of bicuculline or picrotoxin, at doses that do not change the latency to pinch-evoked movement when administered alone, antagonized the suppression of noxious-evoked movement produced by halothane concentrations equal to or greater than MAC. These results suggest that enhancement of GABAA receptor-mediated transmission within the spinal cord contributes to halothane's ability to suppress nocifensive movements.
Mason
P
P
Department of Pharmacological and Physiological Sciences, University of Chicago, Illinois 60637, USA.
Owens
C A
CA
Hammond
D L
DL
D000700:Analgesics / Q000037:antagonists & inhibitors*; D018685:Anesthetics, Inhalation / Q000037:antagonists & inhibitors*; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D058787:GABA-A Receptor Antagonists; D006221:Halothane / Q000037:antagonists & inhibitors*; D007278:Injections, Spinal; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000502:physiology; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology
D000700:Analgesics; D018685:Anesthetics, Inhalation; D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; D018009:Receptors, Glycine; D006221:Halothane