Sex, estrous cycle, and hormone regulation of CYP2D in the brain alters oxycodone metabolism and analgesia.
Sex, estrous cycle, and hormone regulation of CYP2D in the brain alters oxycodone metabolism and analgesia.
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DOI：
10.1016/j.bcp.2022.114949
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发表时间：
2022-04
影响因子：
5.8
通讯作者：
Tyndale, Rachel F.
中科院分区：
文献类型：
--
作者：
Arguelles, Nicole;Richards, Janielle;El-Sherbeni, Ahmed A.;Miksys, Sharon;Tyndale, Rachel F.
阿片类药物和许多中枢活性药物由细胞色素P450 2D(细胞色素P450 2D)代谢。脑羟考酮的镇痛作用存在性别和动情周期的差异。在这里，我们研究了大脑中CYP2D对性别、发情周期和激素调节的选择性作用的机制。雌雄(动情期和间情期)大鼠在给予羟考酮(或羟吗酮，阴性对照)前24小时脑室注射心得安或载体药物心得安。去卵巢和假手术的女性不接受任何处理、雌二醇、黄体酮或赋形剂。用甩尾潜伏期测定镇痛作用，用微透析法测定脑部药物和代谢物浓度。数据分析采用双因素方差分析或混合方差分析。在心得安(相对于赋形剂)抑制和口服羟考酮后，动情期男性和女性的脑羟考酮浓度和镇痛作用有更大的增加，脑内羟考酮/羟考酮的比率(大脑中的一种体内的CYP2D表型)比女性有更大的下降；对血浆药物浓度没有影响。普奈洛尔预处理、性别或口服羟吗酮(非CYP2D底物)后的周期对脑羟吗酮浓度或镇痛没有影响。卵巢摘除后普奈洛尔的预治疗对脑羟考酮浓度或镇痛作用没有影响，在卵巢切除的女性接受雌二醇治疗后，这一作用恢复，但不影响孕酮治疗。性别、周期和雌二醇对脑内CYP2D的调节反过来又改变了脑羟考酮的浓度和反应，这可能是导致对包括阿片类药物在内的多种中枢作用的CYP2D底物药物反应的个体间差异较大的原因。
Opioids, and numerous centrally active drugs, are metabolized by cytochrome P450 2D (CYP2D). There are sex and estrous cycle differences in brain oxycodone analgesia. Here we investigated the mechanism examining the selective role of CYP2D in the brain on sex, estrous cycle, and hormonal regulation. Propranolol, CYP2D-specific mechanism-based inhibitor, or vehicle was delivered into cerebral ventricles 24 hours before administering oxycodone (or oxymorphone, negative control) orally to male and female (in estrus and diestrus) rats. Ovariectomized and shamoperated females received no treatment, estradiol, progesterone or vehicle. Analgesia was measured using tail-flick latency, and brain drug and metabolite concentrations were measured by microdialysis. Data were analyzed by two-way or mixed ANOVA. Following propranolol (versus vehicle) inhibition and oral oxycodone, there were greater increases in brain oxycodone concentrations and analgesia, and greater decreases in brain oxymorphone/oxycodone ratios (an in vivo phenotype of CYP2D in brain) in males and females in estrus, compared to females in diestrus; with no impact on plasma drug concentrations. There was no impact of propranolol pretreatment, sex, or cycle after oral oxymorphone (non-CYP2D substrate) on brain oxymorphone concentrations or analgesia. There was no impact of propranolol pre-treatment following ovariectomy on brain oxycodone concentrations or analgesia, which was restored in ovariectomized females following estradiol, but not progesterone, treatment. Sex, cycle, and estradiol regulation of CYP2D in brain in turn altered brain oxycodone concentration and response, which may contribute to the large inter-individual variation in response to the numerous centrally acting CYP2D substrate drugs, including opioids.
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影响因子：
7.6
作者：
McMillan, Douglas M.;Tyndale, Rachel F.
通讯作者：
Tyndale, Rachel F.
影响因子：
4.7
作者：
Mann, Amandeep;Miksys, Sharon;Tyndale, Rachel F.
通讯作者：
Tyndale, Rachel F.
DOI：
10.1097/00008571-200208000-00007
发表时间：
2002-08-01
期刊：
PHARMACOGENETICS
影响因子：
--
作者：
Rau, T;Heide, R;Eschenhagen, T
通讯作者：
Eschenhagen, T
影响因子：
5.3
作者：
Tanapat, P;Hastings, NB;Gould, E
通讯作者：
Gould, E
影响因子：
4.7
作者：
Miksys, S;Rao, Y;Tyndale, RF
通讯作者：
Tyndale, RF