Desensitization to the behavioral effects of α2-adrenergic agonists in rats

Abstract

Background: The analgesic and sedative-hypnotic utility of the α2 agonists clonidine and dexmedetomidine are currently being investigated. Both compounds exert their behavioral responses by activating central α2 adrenoceptors, albeit with different selectivities and efficacies. Furthermore, the analgesic and hypnotic behavioral responses are produced at different sites and may be affected independently of one another. A series of studies was conducted in rats to determine (1) whether tolerance and cross- tolerance develop to the analgesic actions of clonidine or dexmedetomidine; (2) how the number of available α2 adrenoceptors affects the analgesic response tn dexmedetomidine and clonidine; and (3) how the number of available α2 adrenoceptor affects the hypnotic response tn dexmedetomidine. Methods: Rats were administered equianalgesic doses of dexmedetomidine or clonidine continuously, subcutaneously by osmotic minipumps. After 7 days the analgesic response to acutely administered dexmedetomidine or clonidine at median effective analgesic doses was assessed by the tail-flick latency response. The number of α2 adrenoceptors in the spinal cord was diminished in a dose-dependent manner by covalent modification with a noncompetitive receptor blocker, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). Recovery of the tail-flick latency response to clonidine and dexmedetomidine was determined and correlated to the recovery of receptor density as assessed by radiolabeled-ligand binding studies. The α2 adrenoceptor population in the locus ceruleus of rats was depleted with EEDQ, and recovery of the hypnotic response (as assessed by the loss of righting reflex) to dexmedetomidine was determined and correlated to the recovery of receptor density. Results: After 7 days of chronic treatment with dexmedetomidine, analgesic responses to dexmedetomidine and clonidine remained unaltered. However, chronic treatment with clonidine significantly decreased the analgesic effect of clonidine, whereas the analgesic effect to dexmedetomidine was unaffected. In the EEDQ experiments, the analgesic response to dexmedetomidine was restored to normal when 44% of the α2 adrenoceptors in the spinal cord were available for agonist binding: comparatively more α2 adrenoceptors (77%) were required for the analgesic response to clonidine to be restored. The recovery of the hypnotic response to dexmedetomidine after EEDQ treatment was retarded when compared with the recovery of the analgesic response to that compound. Greater than 77% of α2 adrenoceptors in the locus ceruleus must be available for the hypnotic response to α2 agonists to be expressed. Conclusions: Fewer α2 adrenoceptors need to be available for analgesia to be produced by dexmedetomidine compared with the number required for analgesia by clonidine. This difference should result in less tolerance in the analgesic response tn dexmedetomidine than to clonidine with chronic use. Dexmedetomidine requires fewer α2 adrenoceptors to elicit an analgesic response than it does to elicit a hypnotic response. Thus the analgesic properties of α2-adrenergic agonists persist after the hypnotic response has been attenuated after chronic α2 agonist administration.