The respiratory depressant effects of mitragynine are limited by its conversion to 7-OH mitragynine.
The respiratory depressant effects of mitragynine are limited by its conversion to 7-OH mitragynine.
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米曲宁的呼吸抑制作用因其转化为7-羟基米曲宁而受到限制。
DOI：
10.1111/bph.15832
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发表时间：
2022-07
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
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作者：
Mitragynine是美丽Mitragyna speciosa（kratom）中的主要生物碱，是μ阿片受体的部分激动剂。mitragynine的CYP 3A依赖性氧化产生代谢产物7-OH mitragynine，一种更有效的μ受体激动剂。虽然mitragynine和7-OH mitragynine都可以诱导小鼠的抗伤害感受，但最近的证据表明，作为代谢产物形成的7-OH mitragynine足以解释mitragynine的抗伤害感受作用。然而，尚未研究7-OH mitragynine诱导μ受体依赖性呼吸抑制的能力。使用全身体积描记法测量清醒、自由活动的雄性CD-1小鼠的呼吸。使用热板试验测量抗伤害感受。口服吗啡、mitragynine、7-OH mitragynine和CYP 3A抑制剂酮康唑。Mitragynine的呼吸抑制作用显示出天花板效应，即剂量高于10 mg·kg-1产生相同水平的作用。相反，7-OH mitragynine对小鼠呼吸产生剂量依赖性作用。在等剂量下，mitragynine和7-OH mitragynine均诱导延长的抗伤害感受。抑制CYP 3A可降低mitragynine诱导的呼吸抑制和抗伤害感受，而不影响7-OH mitragynine的作用。mitragynine的抗伤害作用和呼吸抑制作用部分是由于其代谢转化为7-OH mitragynine。mitragynine转化为其活性代谢物的速率有限，导致mitragynine诱导的呼吸抑制的内在上限效应。这些数据表明，在高剂量下的这种“代谢饱和”可能是mitragynine作为阿片类镇痛药的安全性改善的基础。
Mitragynine, the major alkaloid in Mitragyna speciosa (kratom), is a partial agonist at the μ opioid receptor. CYP3A‐dependent oxidation of mitragynine yields the metabolite 7‐OH mitragynine, a more efficacious μ receptor agonist. While both mitragynine and 7‐OH mitragynine can induce anti‐nociception in mice, recent evidence suggests that 7‐OH mitragynine formed as a metabolite is sufficient to explain the anti‐nociceptive effects of mitragynine. However, the ability of 7‐OH mitragynine to induce μ receptor‐dependent respiratory depression has not yet been studied. Respiration was measured in awake, freely moving, male CD‐1 mice, using whole body plethysmography. Anti‐nociception was measured using the hot plate assay. Morphine, mitragynine, 7‐OH mitragynine and the CYP3A inhibitor ketoconazole were administered orally. The respiratory depressant effects of mitragynine showed a ceiling effect, whereby doses higher than 10 mg·kg−1 produced the same level of effect. In contrast, 7‐OH mitragynine induced a dose‐dependent effect on mouse respiration. At equi‐depressant doses, both mitragynine and 7‐OH mitragynine induced prolonged anti‐nociception. Inhibition of CYP3A reduced mitragynine‐induced respiratory depression and anti‐nociception without affecting the effects of 7‐OH mitragynine. Both the anti‐nociceptive effects and the respiratory depressant effects of mitragynine are partly due to its metabolic conversion to 7‐OH mitragynine. The limiting rate of conversion of mitragynine into its active metabolite results in a built‐in ceiling effect of the mitragynine‐induced respiratory depression. These data suggest that such ‘metabolic saturation’ at high doses may underlie the improved safety profile of mitragynine as an opioid analgesic.
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影响因子：
6.7
作者：
Crews KR;Monte AA;Huddart R;Caudle KE;Kharasch ED;Gaedigk A;Dunnenberger HM;Leeder JS;Callaghan JT;Samer CF;Klein TE;Haidar CE;Van Driest SL;Ruano G;Sangkuhl K;Cavallari LH;Müller DJ;Prows CA;Nagy M;Somogyi AA;Skaar TC
通讯作者：
Skaar TC
DOI：
10.1038/npp.2015.201
发表时间：
2016-02
期刊：
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
影响因子：
--
作者：
Hill R;Lyndon A;Withey S;Roberts J;Kershaw Y;MacLachlan J;Lingford-Hughes A;Kelly E;Bailey C;Hickman M;Henderson G
通讯作者：
Henderson G
影响因子：
7.3
作者：
Chakraborty S;Uprety R;Slocum ST;Irie T;Le Rouzic V;Li X;Wilson LL;Scouller B;Alder AF;Kruegel AC;Ansonoff M;Varadi A;Eans SO;Hunkele A;Allaoa A;Kalra S;Xu J;Pan YX;Pintar J;Kivell BM;Pasternak GW;Cameron MD;McLaughlin JP;Sames D;Majumdar S
通讯作者：
Majumdar S
影响因子：
7.3
作者：
Hill R;Disney A;Conibear A;Sutcliffe K;Dewey W;Husbands S;Bailey C;Kelly E;Henderson G
通讯作者：
Henderson G
影响因子：
2.5
作者：
Basiliere, Stephanie;Kerrigan, Sarah
通讯作者：
Kerrigan, Sarah