ROLE OF PERTUSSIS-TOXIN-SENSITIVE G-PROTEINS IN THE ANALGESIC AND ANESTHETIC ACTIONS OF ALPHA(2)-ADRENERGIC AGONISTS IN THE RAT

Background: alpha(2) Adrenoceptors are coupled to G-proteins sensitive to pertussis toxin (PTX) in the locus coeruleus. At this site, the hypnotic response to dexmedetomidine, an alpha 2 agonist, can be blocked by pretreatment with PTX. G-proteins sensitive to PTX may also be involved in the transduction of anesthetic and analgesic responses to alpha(2) agonists at supraspinal or spinal sites. To address this question the effects of pretreatment with PTX administered intracerebroventricularly, intrathecally, or a combination of the two were examined on the MAC for halothane, and the anesthetic-sparing and analgesic effects of a systemically administered alpha(2) agonist, dexmedetomidine. Methods: Rats were cannulated intracerebroventricularly, intrathecally, and with a combination of intracerebroventricular/intrathecal and treated with PTX (0 and 2.5 mu g intracerebroventricularly; 0 or 0.5 mu g intrathecally; 0 + 0 or 2.5 + 0.5 intracerebroventricular-intrathecal)). After 7 days, either the analgesic (tail-nick latency) or the MAC-sparing effects of a calculated 50% effective dose of dexmedetomidine were measured. To confirm that intracerebroventricularly administered PTX was effective, ribosylation of G-proteins was assessed in periventricular brain tissue. Results: The analgesic action of dexmedetomidine was blocked by PTX intrathecally but not by PTX via the intracerebroventricular route. The MAC-sparing action of dexmedetomidine was not blocked by PTX via the intrathecal or intracerebroventricular routes alone or in combination. Yet, intracerebroventricularly administered PTX effectively ribosylated the G-proteins. Conclusions: Taken together with the authors' previous report, these data suggest that the hypnotic and the analgesic responses to dexmedetomidine are transduced via PTX-sensitive G-protein-coupled alpha(2) adrenoceptors but at separate sites (analgesic-spinal; hypnotic-locus coeruleus). Further studies are needed to localize the precise site(s) for the MAC-sparing effect of dexmedetomidine and to establish whether PTX-sensitive G-proteins are involved in this response.