Sato Yuki, Onaka Tatsushi, Kobayashi Eiji, Seo Norimasa
Department of Anesthesiology, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan.
Anesth Analg. 2007 Nov;105(5):1489-93, table of contents. doi: 10.1213/01.ane.0000286173.60987.72.
The calcineurin inhibitor, cyclosporine, is widely used for preventing allograft rejection in organ transplantation. Systemically administered cyclosporine is prevented from entering into the brain by the action of P-glycoprotein, encoded by the multidrug resistant 1 (mdr1) gene. However, in many transplant recipients, cyclosporine administration causes postoperative neuropsychological side effects, such as confusion, depression, and anxiety. Recently, calcineurin-inhibitor-induced pain syndrome, characterized by severe pain in the lower limbs, has also been recognized in both organ and stem-cell transplantations.
In the present study, we developed behavioral models in wild-type and mdr1a knockout mice to reveal whether peripheral or central cyclosporine alters pain reactions and hypnotic sensitivities. Cyclosporine's central actions can be better evaluated in mdr1a knockout mice that lack P-glycoprotein. After intraperitoneal administration of cyclosporine, we examined tail-flick latency in the tail immersion test, or duration of loss of righting reflex in response to pentobarbital and ketamine.
In wild-type mice, the highest dose of cyclosporine significantly prolonged the duration of loss of righting reflex in response to ketamine, but not to pentobarbital. On the other hand, the lower doses of cyclosporine significantly increased both pentobarbital- and ketamine-induced sleep durations in mdr1a knockout mice. Tail-flick latencies in the tail immersion test were significantly shortened in both wild-type and knockout mice by the administration of cyclosporine.
Our results suggest that centrally accumulated cyclosporine enhances the hypnotic response to pentobarbital and ketamine, but peripheral cyclosporine induces hyperalgesia.
钙调神经磷酸酶抑制剂环孢素广泛用于预防器官移植中的同种异体移植排斥反应。全身给药的环孢素会受到多药耐药1（mdr1）基因编码的P-糖蛋白的作用，从而无法进入大脑。然而，在许多移植受者中，环孢素给药会引起术后神经心理副作用，如意识模糊、抑郁和焦虑。最近，在器官移植和干细胞移植中均已认识到以双下肢剧痛为特征的钙调神经磷酸酶抑制剂诱导的疼痛综合征。
在本研究中，我们在野生型和mdr1a基因敲除小鼠中建立行为模型，以揭示外周或中枢环孢素是否会改变疼痛反应和催眠敏感性。在缺乏P-糖蛋白的mdr1a基因敲除小鼠中可以更好地评估环孢素的中枢作用。腹腔注射环孢素后，我们在尾浸试验中检测甩尾潜伏期，或检测对戊巴比妥和氯胺酮的翻正反射消失持续时间。
在野生型小鼠中，最高剂量的环孢素显著延长了对氯胺酮的翻正反射消失持续时间，但对戊巴比妥则没有。另一方面，较低剂量的环孢素显著增加了mdr1a基因敲除小鼠中戊巴比妥和氯胺酮诱导的睡眠时间。在野生型和基因敲除小鼠中，环孢素给药均显著缩短了尾浸试验中的甩尾潜伏期。
我们的结果表明，中枢蓄积的环孢素增强了对戊巴比妥和氯胺酮的催眠反应，但外周环孢素会诱导痛觉过敏。
