CENTRAL ALPHA-1-ADRENOCEPTOR STIMULATION FUNCTIONALLY ANTAGONIZES THE HYPNOTIC RESPONSE TO DEXMEDETOMIDINE, AN ALPHA-2-ADRENOCEPTOR AGONIST

Previously, we demonstrated that dexmedetomidine, an alpha-2 agonist, produces a hypnotic-anesthetic response in rats via activation of central alpha-2 adrenoceptors and that this response could be enhanced by the alpha-1 antagonist prazosin. In the current experiment we investigated whether central alpha-1 adrenoceptor stimulation antagonizes the alpha-2 adrenoceptor-mediated hypnotic response. Cirazoline, an alpha-1 adrenoceptor agonist that partitions into the central nervous system, attenuated dexmedetomidine's hypnotic response whether administered systemically (0.3-1 mg.kg-1 intraperitoneally [ip]) or centrally (0.1 mg.kg-1 intracerebroventricularly). Prazosin, an alpha-1 adrenoceptor antagonist that effectively crosses the blood-brain barrier, fully blocked cirazoline's attenuating effect on dexmedetomidine-induced hypnosis, whereas doxazosin, which partitions poorly into the brain, did not block cirazoline's effect. Administration of phenylephrine, 0.3-3 mg.kg-1 ip, an alpha-1 adrenoceptor agonist that does not penetrate into the brain, did not attenuate dexmedetomidine's hypnotic effect. These results indicate that central alpha-1-adrenoceptor stimulation functionally antagonizes the hypnotic response to an alpha-2-adrenoceptor agonist. These data underscore the important requirement for alpha-2 adrenoceptor selectivity if these agonists are to be useful in the anesthetic setting.