Guo T Z, Reid K, Davies M F, Nacif-Coelho C, Rabin B C, Gonzalez F, Maze M
Department of Anesthesia, Stanford University, Veterans Affairs, Palo Alto Health Care Systems, California, USA.
Anesthesiology. 1998 Jun;88(6):1634-42. doi: 10.1097/00000542-199806000-00028.
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 alpha2-adrenergic agonist, were studied in rats.
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 microg/kg given intraperitoneally, on the duration of loss of righting reflex was determined. The tail flick latency response was determined before and after 50 microg/kg dexmedetomidine. The minimum anesthetic concentration of halothane and the central norepinephrine turnover rate were determined before and after administration of 30 microg/kg dexmedetomidine. Changes in the affinity and density of the alpha2-adrenergic receptor in locus coeruleus and spinal cord also were determined.
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 alpha2 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 alpha1-adrenergic antagonist prazosin at 1 or 5 mg/kg completely (minimum anesthetic concentration reduction), almost completely (antinociceptive), or partially (hypnotic) restored responsiveness to normal.
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 alpha1-adrenergic mechanism.
在大鼠中研究了长期给予三环类抗抑郁药地昔帕明对短期给予右美托咪定（一种高度选择性α2肾上腺素能激动剂）的催眠、抗伤害感受、麻醉节省及中枢去甲肾上腺素周转抑制作用的影响。
大鼠接受为期3或4周的地昔帕明（10mg/kg）或生理盐水每日两次给药。测定腹腔注射催眠剂量右美托咪定（250μg/kg）对翻正反射消失持续时间的影响。在给予50μg/kg右美托咪定前后测定甩尾潜伏期反应。在给予30μg/kg右美托咪定前后测定氟烷的最低肺泡有效浓度及中枢去甲肾上腺素周转率。还测定了蓝斑和脊髓中α2肾上腺素能受体亲和力和密度的变化。
地昔帕明治疗使右美托咪定诱导的翻正反射消失持续时间缩短67%，并消除了右美托咪定的抗伤害感受作用。右美托咪定使对照组最低肺泡有效浓度降低55%，但在接受地昔帕明治疗的大鼠中未降低。地昔帕明未改变催眠（蓝斑）或抗伤害感受（脊髓）反应部位α2受体的受体密度或结合亲和力。地昔帕明治疗3周后，右美托咪定在蓝斑中的中枢去甲肾上腺素周转率未见降低。1或5mg/kg的α1肾上腺素能拮抗剂哌唑嗪可完全（最低肺泡有效浓度降低）、几乎完全（抗伤害感受）或部分（催眠）恢复反应性至正常。
这些数据表明，地昔帕明治疗可诱导对右美托咪定的催眠、镇痛和降低最低肺泡有效浓度特性反应性降低，但对其抑制中枢去甲肾上腺素周转特性无反应。反应性降低似乎涉及α1肾上腺素能机制。
