摘要譯文（供參考）
哌醋甲酯逆轉(zhuǎn)右美托咪定與氯胺酮誘導的鎮(zhèn)靜作用
背景：
右美托咪定和氯胺酮在人體中具有較長的消除半衰期，且無臨床批準的拮抗劑。哌醋甲酯通過抑制多巴胺能和去甲腎上腺素能神經(jīng)遞質(zhì)的再攝取轉(zhuǎn)運蛋白來增強多巴胺能和去甲腎上腺素能神經(jīng)遞質(zhì)。先前在大鼠中的研究表明，靜脈注射哌醋甲酯可誘導異氟醚和丙泊酚全身麻醉蘇醒。認為這2種麻醉劑主要通過增強抑制性γ-氨基丁酸A型(GABAA)受體起作用。在本研究中，我們在大鼠中測試了哌醋甲酯在低劑量和高劑量右美托咪定(一種α-2腎上腺素能受體激動劑)和氯胺酮(一種N-甲基-D-天冬氨酸[NMDA]受體拮抗劑)分別誘導鎮(zhèn)靜和意識喪失后的行為和神經(jīng)生理學影響。
方法：
所有實驗均使用成年雄性和雌性Sprague-Dawley大鼠(共32只)，所有藥物均以交叉、盲態(tài)實驗設計靜脈給藥。采用曠場試驗(n=16)檢測了右美托咪定(10μg/kg)或氯胺酮(10mg/kg)與或不與哌醋甲酯(5mg/kg)一起鎮(zhèn)靜給藥后的運動(n=16)。在第二組大鼠(n=8)中評估了高劑量右美托咪定(50μg/kg)或高劑量氯胺酮(50mg/kg)加或不加哌醋甲酯(1-5mg/kg)后翻正反射的恢復情況。最后，在第三組大鼠(n=8)中，記錄額腦電圖(EEG)，用于在低劑量和高劑量右美托咪定和氯胺酮與或不與哌醋甲酯的情況下進行光譜分析。
結(jié)果：
低劑量右美托咪定使大鼠的運動減少94%。低劑量右美托咪定后哌醋甲酯可恢復運動(秩差=88.5，95%可信區(qū)間[CI]，70.8-106)，與多巴胺D1受體拮抗劑聯(lián)合給藥可阻斷該效應(秩差=86.2，95%CI，68.6-104)。低劑量氯胺酮可使大鼠的翻正反射潛伏期一過性減低58%，哌醋甲酯對其無改善作用，但對大劑量右美托咪定和氯胺酮后翻正反射潛伏期的恢復均無影響。額葉EEG分析顯示哌醋甲酯逆轉(zhuǎn)了低劑量右美托咪定引起的光譜變化(F[8，87]=3.27，P=.003)，但高劑量右美托咪定后僅產(chǎn)生短暫的變化。低劑量或高劑量氯胺酮給藥后，哌醋甲酯均未引起腦電圖的光譜改變。
結(jié)論：
哌醋甲酯逆轉(zhuǎn)右美托咪定誘導的鎮(zhèn)靜行為和神經(jīng)生理學相關(guān)性，但不逆轉(zhuǎn)無意識。相反，哌醋甲酯不影響氯胺酮后大鼠的鎮(zhèn)靜、意識喪失和腦電圖特征。這些發(fā)現(xiàn)表明哌醋甲酯可能有效地逆轉(zhuǎn)右美托咪定在人體中的鎮(zhèn)靜。
原文摘要
Methylphenidate Reversal of Dexmedetomidine-Induced Versus Ketamine-Induced Sedation in Rats
Background: Dexmedetomidine and ketamine have long elimination half-lives in humans and have no clinically approved reversal agents. Methylphenidate enhances dopaminergic and noradrenergic neurotransmission by inhibiting reuptake transporters for these arousal-promoting neurotransmitters. Previous studies in rats demonstrated that intravenous methylphenidate induces emergence from isoflurane and propofol general anesthesia. These 2 anesthetics are thought to act primarily through enhancement of inhibitory Gamma-aminobutyric acid type A (GABAA) receptors. In this study, we tested the behavioral and neurophysiological effects of methylphenidate in rats after low and high doses of dexmedetomidine (an alpha-2 adrenergic receptor agonist) and ketamine (an N-methyl-D-aspartate [NMDA] receptor antagonist) that induce sedation and unconsciousness, respectively.
Methods: All experiments used adult male and female Sprague-Dawley rats (n = 32 total) and all drugs were administered intravenously in a crossover, blinded experimental design. Locomotion after sedating doses of dexmedetomidine (10 μg/kg) or ketamine (10 mg/kg) with and without methylphenidate (5 mg/kg) was tested using the open field test (n = 16). Recovery of righting reflex after either high-dose dexmedetomidine (50 μg/kg) or high-dose ketamine (50 mg/kg) with and without methylphenidate (1-5 mg/kg) was assessed in a second cohort of rats (n = 8). Finally, in a third cohort of rats (n = 8), frontal electroencephalography (EEG) was recorded for spectral analysis under both low and high doses of dexmedetomidine and ketamine with and without methylphenidate.
Results: Low-dose dexmedetomidine reduced locomotion by 94% in rats. Methylphenidate restored locomotion after low-dose dexmedetomidine (rank difference = 88.5, 95% confidence interval [CI], 70.8-106) and the effect was blocked by coadministration with a dopamine D1 receptor antagonist (rank difference = 86.2, 95% CI, 68.6-104). Low-dose ketamine transiently attenuated mobility by 58% and was not improved with methylphenidate. Methylphenidate did not affect the return of righting reflex latency in rats after high-dose dexmedetomidine nor ketamine. Frontal EEG analysis revealed that methylphenidate reversed spectral changes induced by low-dose dexmedetomidine (F [8,87] = 3.27, P = .003) but produced only transient changes after high-dose dexmedetomidine. Methylphenidate did not induce spectral changes in the EEG after low- or high-dose ketamine.
Conclusions: Methylphenidate reversed behavioral and neurophysiological correlates of sedation, but not unconsciousness, induced by dexmedetomidine. In contrast, methylphenidate did not affect sedation, unconsciousness, nor EEG signatures in rats after ketamine. These findings suggest that methylphenidate may be efficacious to reverse dexmedetomidine sedation in humans.
