Chronic administration of an α2 adrenergic agonist desensitizes rats to the anesthetic effects of dexmedetomidine

Abstract

α 2 adrenergic agonists are being administered perioperatively to facilitate the anesthetic management of the surgical patient. In some clinical settings, use of α 2 adrenergic agonists has been extended into the postoperative period to prolong the patients' sedative and stress-free state. We studied whether the administration of α 2 adrenergic agonists over an extended period of time would result in “desensitization” to the central actions of α 2 adrenergic agonists. Male Sprague-Dawley rats were administered dexmedetomidine, a highly selective α 2 adrenergic agonist, at rates varying between 1 and 10 μg·kg −1·h −1via a chronically implanted SC osmotic pump. Spontaneous locomotor activity, tested in an open-field box, was significantly lower in both 3- and 10-μg·kg −1·h −1 treatment groups but returned to normal by the second or sixth day, respectively. The hypnotic response to dexmedetomidine IP was decreasedin the 10-μg·kg −1·h −1 dose group from the second day, and by the fourth day in the 3-μg·kg −1·h −1 group. Recovery from the desensitized state was rapid and occurred on the third day after pump removal in the 3-μg·kg −1·h(su−1) group and by the fifth day after pump removal in the 10-μg·kg −1·h −1 dose group. By using a higher dose of dexmedetomidine IP (250 μg·kg in lieu of 100 μg/kg) at day 7 in “tolerant” rats, the hypnotic response could partially be “restored” towards normal. An attenuated hypnotic response could still be demonstrated even when dexmedetomidine was administered directly into the locus coeruleus (LC) in rats pretreated chronically with dexmedetomidine. In no case could hypnotic responsiveness be restored to normal by pretreating with the α 1 adrenergic antagonist prazosin. The minimum anesthetic concentration (MAC) for halothane was not altered in the “tolerant” rats. These data indicate that hyporesponsiveness develops to the central depressant effects of an α 2 adrenergic receptor agonist, through a pharmacodynamic mechanism.