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 hy pnotic response to dexmedetomidine, an alpha 2 agonist, can be blocked by pretreatment with PTX. G-proteins sensitive to PTX may also be inv olved in the transduction of anesthetic and analgesic responses to alp ha(2) agonists at supraspinal or spinal sites. To address this questio n the effects of pretreatment with PTX administered intracerebroventri cularly, intrathecally, or a combination of the two were examined on t he MAC for halothane, and the anesthetic-sparing and analgesic effects of a systemically administered alpha(2) agonist, dexmedetomidine. Met hods: Rats were cannulated intracerebroventricularly, intrathecally, a nd with a combination of intracerebroventricular/intrathecal and treat ed with PTX (0 and 2.5 mu g intracerebroventricularly; 0 or 0.5 mu g i ntrathecally; 0 + 0 or 2.5 + 0.5 intracerebroventricular-intrathecal)) . After 7 days, either the analgesic (tail-nick latency) or the MAC-sp aring effects of a calculated 50% effective dose of dexmedetomidine we re measured. To confirm that intracerebroventricularly administered PT X was effective, ribosylation of G-proteins was assessed in periventri cular brain tissue. Results: The analgesic action of dexmedetomidine w as blocked by PTX intrathecally but not by PTX via the intracerebroven tricular route. The MAC-sparing action of dexmedetomidine was not bloc ked by PTX via the intrathecal or intracerebroventricular routes alone or in combination. Yet, intracerebroventricularly administered PTX ef fectively ribosylated the G-proteins. Conclusions: Taken together with the authors' previous report, these data suggest that the hypnotic an d the analgesic responses to dexmedetomidine are transduced via PTX-se nsitive G-protein-coupled alpha(2) adrenoceptors but at separate sites (analgesic-spinal; hypnotic-locus coeruleus). Further studies are nee ded to localize the precise site(s) for the MAC-sparing effect of dexm edetomidine and to establish whether PTX-sensitive G-proteins are invo lved in this response.