ANTAGONISM OF THE ANTINOCIFENSIVE ACTION OF HALOTHANE BY INTRATHECAL ADMINISTRATION OF GABA(A) RECEPTOR ANTAGONISTS

Background: The hind brain and the spinal cord, regions that contain h igh concentrations of gamma-aminobutyric acid (GABA) and GABA receptor s, have been implicated as sites of action of inhalational anesthetics . Previous studies have established that general anesthetics potentiat e the effects of gamma-aminobutyric acid at the GABA(A) receptor. It w as therefore hypothesized that the suppression of nocifensive movement s during anesthesia is due to an enhancement of GABA(A) receptor-media ted transmission within the spinal cord. Methods: Rats in which an int rathecal catheter had been implanted 1 week earlier were anesthetized with halothane. Core temperature was maintained at a steady level. Aft er;MAC determination, the concentration of halothane was adjusted to t hat at which the rats last moved in response to tail clamping. Saline, a GABA(A), a GABA(B), or a glycine receptor antagonist was then injec ted intrathecally. The latency to move in response to application of t he 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 s ubsequent 35 min. To determine whether these antagonists altered basel ine response latencies by themselves, another experiment was conducted in which the concentration of halothane was not increased after intra thecal administration of GABA(A) receptor antagonists. Results: Intrat hecal administration of the GABA(A) receptor antagonists bicuculline ( 0.3 mu g) or picrotoxin (0.3, 1.0 mu g) antagonized the suppression of nocifensive movement produced by the small increase in halothane conc entration. In contrast, the antinocifensive effect of the increase in halothane concentration was not attenuated by the GABA(B) receptor ant agonist CGP 35348 or the glycine receptor antagonist strychnine. By th emselves, the GABA(A) receptor antagonists did not alter response late ncy in rats anesthetized with sub-MAC concentrations of halothane. Con clusions: Intrathecal administration of bicuculline or picrotoxin, at doses that do not change the latency to pinch-evoked movement when adm inistered alone, antagonized the suppression of noxious-evoked movemen t produced by halothane concentrations equal to or greater than MAC. T hese results suggest that enhancement of GABA(A) receptor-mediated tra nsmission within the spinal cord contributes to halothane's ability to suppress nocifensive movements.