PERTURBATION OF ION-CHANNEL CONDUCTANCE ALTERS THE HYPNOTIC RESPONSE TO THE ALPHA-ADRENERGIC AGONIST DEXMEDETOMIDINE IN THE LOCUS COERLEUS OF THE RAT

Background: The alpha(2)-adrenergic agonists are members of a novel class of hypnotic-anesthetic agents that selectively bind to cu, adrenoceptors in the locus coeruleus (LC) to initiate their pharmacologic action. The postreceptor molecular mechanism of the hypnotic action of alpha(2)-adrenergic agonists remains unknown. In this study we addressed the role of conductance through a variety of calcium and potassium ion channels in the hypnotic action of dexmedetomidine in the LC of the rat. Methods: Cannulas were inserted stereotactically into the LC of halothane-anesthetized rats (n = 318). After at least 48 h, rats were tested for loss of righting reflex in response to administration of the alpha(2)-adrenergic agonist dexmedetomidine at a hypnotic (7.0 mu g LC) or subhypnotic (3.5 mu g LC) dose. To establish the mediating role of various species of calcium and potassium ion channels in the hypnotic response, rats were pretreated with the following drugs before the administration of dexmedetomidine LC: S(+)202791 (L-type calcium-channel activator), nifedipine and R(-)202791 (L-type calcium-channel blocker), SNX 111 (N-type calcium-channel blocker), SNX 230 (P-type calcium-channel blocker), quinine (calcium-activated and voltage-gated potassium-channel blocker), charybdotoxin (calcium-activated potassium-channel blocker), dendrotoxin (voltage-gated potassium-channel blocker), or glybenclamide (adenosine triphosphate-sensitive potassium-channel blocker). The drugs were used in doses not causing behavioral effects that could have confounded the interpretation of loss of righting reflex. Results: SNX 230 and the dihydropyridines nifedipine and R(-)202791 produced loss of righting reflex in the presence of a subhypnotic dose of dexmedetomidine. The hypnotic-enhancing effects of the dihydropyridines could be blocked with S(+)202791, which also diminished loss of righting reflex in response to dexmedetomidine 7.0 mu g LC. Quinine, dendrotoxin, and charybdotoxin each attenuated the hypnotic response to dexmedetomidine 7.0 mu g LC. The hypnotic response to dexmedetomidine was not significantly altered by SNX 111 or glybenclamide. Conclusions: Inhibition of ion conductance through L- or P-type calcium channels and facilitation of conductance through voltage-gated or calcium-activated potassium channels may be involved in the mechanism of hypnotic action of alpha(2)-adrenergic agonists. These changes in ion conductance were capable of producing membrane hyperpolarization and decreasing neuronal excitability. There was no evidence for the involvement of adenosine triphosphate-sensitive potassium channels or N-type calcium channels in the hypnotic response to dexmedetomidine.