Chronic desipramine treatment desensitizes the rat to anesthetic and antinociceptive effects of the α₂-adrenergic agonist dexmedetomidine

Introduction: The effects of long-term administration of the tricyclic antidepressant agent desipramine on the hypnotic, antinociceptive, anesthetic-sparing, and central norepinephrine turnover suppressant action of short-term dexmedetomidine, a highly selective α₂-adrenergic agonist, were studied in rats. Methods: Rats were given a 3- or 4-week course of twice daily administration of desipramine, 10 mg/kg, or saline. The effect of a hypnotic dose of dexmedetomidine, 250 μg/kg given intraperitoneally, on the duration of loss of righting reflex was determined. The tail flick latency response was determined before and after 50 μg/kg dexmedetomidine. The minimum anesthetic concentration of halothane and the central norepinephrine turnover rate were determined before and after administration of 30 μg/kg dexmedetomidine. Changes in the affinity and density of the α₂-adrenergic receptor in locus coeruleus and spinal cord also were determined. Results: Treatment with desipramine decreased dexmedetomidine-induced loss of righting reflex duration by 67% and eliminated the antinociceptive effect of dexmedetomidine. Dexmedetomidine produced a 55% decrease in minimum anesthetic concentration in the control group but no reduction in desipramine-treated rats. Desipramine did not change the receptor density or binding affinity of α₂ receptors at the site for hypnotic (locus coeruleus) or antinociceptive (spinal cord) responses. No decrement in the central norepinephrine turnover rate was noted in the locus coeruleus of dexmedetomidine after 3 weeks of treatment with desipramine. The α₁- adrenergic antagonist prazosin at 1 or 5 mg/kg completely (minimum anesthetic concentration reduction), almost completely (antinociceptive), or partially (hypnotic) restored responsiveness to normal. Conclusions: These data indicate that treatment with desipramine induces hyporesponsiveness to the hypnotic, analgesic, and minimum anesthetic concentration-reducing, but not to the suppression of central norepinephrine turnover, properties of dexmedetomidine. The hyporesponsiveness appears to involve an α₁-adrenergic mechanism.