DataSheet1_Systemic Administration of Tempol Attenuates the Cardiorespiratory Depressant Effects of Fentanyl.PDF

Fentanyl is a high-potency opioid receptor agonist that elicits profound analgesia and suppression of breathing in humans and animals. To date, there is limited evidence as to whether changes in oxidant stress are important factors in any of the actions of acutely administered fentanyl. This study determined whether the clinically approved superoxide dismutase mimetic, Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl), or a potent antioxidant, N-acetyl-L-cysteine methyl ester (L-NACme), modify the cardiorespiratory and analgesic actions of fentanyl. We examined whether the prior systemic injection of Tempol or L-NACme affects the cardiorespiratory and/or analgesic responses elicited by the subsequent injection of fentanyl in isoflurane-anesthetized and/or freely moving male Sprague-Dawley rats. Bolus injections of Tempol (25, 50 or 100 mg/kg, IV) elicited minor increases in frequency of breathing, tidal volume and minute ventilation. The ventilatory-depressant effects of fentanyl (5 μg/kg, IV) given 15 min later were dose-dependently inhibited by prior injections of Tempol. Tempol elicited dose-dependent and transient hypotension that had (except for the highest dose) resolved when fentanyl was injected. The hypotensive responses elicited by fentanyl were markedly blunted after Tempol pretreatment. The analgesic actions of fentanyl (25 μg/kg, IV) were not affected by Tempol (100 mg/kg, IV). L-NACme did not modify any of the effects of fentanyl. We conclude that prior administration of Tempol attenuates the cardiorespiratory actions of fentanyl without affecting the analgesic effects of this potent opioid. As such, Tempol may not directly affect opioid-receptors that elicit the effects of fentanyl. Whether, the effects of Tempol are solely due to alterations in oxidative stress is in doubt since the powerful antioxidant, L-NACme, did not affect fentanyl-induced suppression of breathing.芬太尼（Fentanyl）是一种强效阿片受体激动剂，可在人类与动物体内引发显著镇痛与呼吸抑制。截至目前，关于急性给予芬太尼的各项作用是否与氧化应激变化密切相关，相关证据仍较为有限。本研究旨在探讨经临床批准的超氧化物歧化酶模拟物替波洛尔（Tempol，4-羟基-2,2,6,6-四甲基哌啶-N-氧基），或是强效抗氧化剂N-乙酰-L-半胱氨酸甲酯（L-NACme），是否会改变芬太尼的心肺与镇痛作用。我们考察了在异氟烷麻醉或自由活动的雄性斯普拉格-道利大鼠中，预先经系统给药的替波洛尔或L-NACme，是否会影响后续注射芬太尼所引发的心肺及/或镇痛反应。静脉推注不同剂量（25、50或100 mg/kg，IV）的替波洛尔后，大鼠的呼吸频率、潮气量与每分通气量仅出现小幅升高。15分钟后给予芬太尼（5 μg/kg，IV）所引发的呼吸抑制效应，可被预先给予的替波洛尔以剂量依赖性方式抑制。替波洛尔可引发剂量依赖性且一过性的低血压，除最高剂量组外，其余组的低血压在芬太尼给药前已恢复。预先给予替波洛尔后，芬太尼引发的低血压反应显著减弱。而替波洛尔（100 mg/kg，IV）并不会影响芬太尼（25 μg/kg，IV）的镇痛作用。L-NACme未对芬太尼的各项作用产生任何改变。我们得出结论，预先给予替波洛尔可减轻芬太尼的心肺作用，却不影响该强效阿片类药物的镇痛效应。由此推测，替波洛尔可能并未直接作用于介导芬太尼效应的阿片受体。鉴于强效抗氧化剂L-NACme并未对芬太尼引发的呼吸抑制产生影响，因此替波洛尔的作用是否完全由氧化应激改变所介导仍存疑。