Sex and Estrous Cycle Differences in Analgesia and Brain Oxycodone Levels.
Sex and Estrous Cycle Differences in Analgesia and Brain Oxycodone Levels.
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DOI：
10.1007/s12035-021-02560-1
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发表时间：
2021-12
影响因子：
5.1
通讯作者：
Tyndale RF
中科院分区：
文献类型：
--
作者：
Arguelles N;Miksys S;Tyndale RF
阿片类药物镇痛的性别差异存在于啮齿类动物和人类中，可能是由于药物和代谢物水平的差异造成的。因此，我们研究了大鼠羟考酮镇痛（伤害感受）的性别和周期差异，并将这些差异与脑和血浆羟考酮和代谢物水平的性别和周期差异相关。由于许多阿片类药物是 CYP2D 酶底物，并且 CYP2D 的变化会改变阿片类药物的水平和反应，因此我们还启动了研究，看看观察到的性别和周期差异是否可能是由于大脑 CYP2D 活性的差异造成的。在羟考酮剂量范围内，与发情期的雄性和雌性相比，处于发情间期的雌性具有更高的镇痛作用（使用甩尾潜伏期）；我们还证明了发情周期对女性镇痛的直接影响。与镇痛作用一致，与发情期的男性和女性相比，发情间期的女性脑内羟考酮水平最高（使用微透析评估）。镇痛与脑羟考酮相关，但与脑羟吗啡酮或去甲羟考酮水平或血浆药物或代谢物水平无关。普萘洛尔（一种基于 CYP2D 机制的抑制剂）与载体预处理相比，在发情期的雄性和雌性中增加了脑羟考酮，并降低了脑羟吗啡酮/羟考酮药物水平比率（大脑中的体内 CYP2D 活性表型），但在发情间期的雌性中则不然。脑羟吗啡酮/羟考酮与镇痛呈负相关。性和动情周期共同影响羟考酮镇痛和脑羟考酮水平，可能是通过调节大脑 CYP2D 羟考酮代谢。由于 CYP2D6 在人类大脑中表达，也许类似的性别和周期影响也发生在人类身上。
Sex differences in opioid analgesia occur in rodents and humans, and could be due to differences in drug and metabolite levels. Thus, we investigated the sex and cycle differences in analgesia (nociception) from oxycodone in rats and related these to sex and cycle differences in brain and plasma oxycodone and metabolite levels. Since numerous opioids are CYP2D enzyme substrates and variation in CYP2D alters opioid drug levels and response, we also initiated studies to see if the sex and cycle differences observed might be due to differences in brain CYP2D activity. Across oxycodone doses, females in diestrus had higher analgesia (using tail flick latency) compared to males and females in estrus; we also demonstrated a direct effect of estrous cycle on analgesia within females. Consistent with the analgesia, females in diestrus had highest brain oxycodone levels (assessed using microdialysis) compared to males and females in estrus. Analgesia correlated with brain oxycodone, but not brain oxymorphone or noroxycodone levels, or plasma drug or metabolite levels. Propranolol (a CYP2D mechanism-based inhibitor), versus vehicle pretreatments, increased brain oxycodone, and decreased brain oxymorphone/oxycodone drug level ratios (an in vivo CYP2D activity phenotype in the brain) in males and females in estrus, but not in females in diestrus. Brain oxymorphone/oxycodone inversely correlated with analgesia. Together, both sex and estrous cycle impact oxycodone analgesia and brain oxycodone levels, likely through regulation of brain CYP2D oxycodone metabolism. As CYP2D6 is expressed in human brain, perhaps similar sex and cycle influences also occur in humans.
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