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首页> 外文期刊>Addiction biology >Rat brain CYP2D activity alters in vivo central oxycodone metabolism, levels and resulting analgesia
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Rat brain CYP2D activity alters in vivo central oxycodone metabolism, levels and resulting analgesia

机译：大鼠脑CYP2D活性在体内中央羟考酮代谢，水平和产生的镇痛中改变

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Oxycodone is metabolized by CYP2D to oxymorphone. Despite oxymorphone being a more potent opioid-receptor agonist, its contribution to oxycodone analgesia may be minor because of low peripheral production, low blood-brain barrier permeability and central nervous system efflux. CYP2D metabolism within the brain may contribute to variation in central oxycodone and oxymorphone levels, thereby affecting analgesia. Brain CYP2D expression and activity are subject to exogenous regulation; nicotine induces rat brain, but not liver, CYP2D consistent with higher brain CYP2D in smokers. We assessed the role of rat brain CYP2D in orally administered oxycodone metabolism (in vivo brain microdialysis) and analgesia (tail-flick test) by inhibiting brain CYP2D selectively with intracerebroventricular propranolol (mechanism-based inhibitor) and inducing brain CYP2D with nicotine. Inhibiting brain CYP2D increased brain oxycodone levels (1.8-fold; P 0.03) and analgesia (1.5-fold AUC(0-60); P 0.001) after oxycodone, while inducing brain CYP2D increased brain oxymorphone levels (4.6-fold; P 0.001) and decreased analgesia (0.8-fold; P 0.02). Inhibiting the induced brain CYP2D reversed the change in oxycodone levels (1.2-fold; P 0.1) and analgesia (1.1-fold; P 0.3). Brain, but not plasma, metabolic ratios were affected by pre-treatments. Peak analgesia was inversely correlated with ex vivo brain (P 0.003), but not hepatic (P 0.9), CYP2D activity. Altering brain CYP2D did not affect analgesia from oral oxymorphone (P 0.9 for AUC(0-60) across all groups), which is not a CYP2D substrate. Thus, brain CYP2D metabolism alters local oxycodone levels and response, suggesting that people with increased brain CYP2D activity may have reduced oxycodone response. Factors that alter individual oxycodone response may be useful for optimizing treatment and minimizing abuse liability.
机译：羟考酮通过CYP2D代谢为羟甲酮。尽管甲状腺手机是一种更有效的阿片类受体激动剂，但由于低外周期生产，低血脑屏障渗透性和中枢神经系统的流出，其对羟考酮镇痛的贡献可能是较小的。 CYP2D大脑中的代谢可能有助于中枢羟考酮和Xymorphone水平的变异，从而影响镇痛。脑CYP2D表达和活性受到外源调节的影响;尼古丁诱导大鼠大脑，但不是肝脏，CYP2D在吸烟者中与高脑CYP2D一致。我们评估了大鼠脑CYP2D在口服羟考酮代谢（体内脑微透析）和镇痛（尾部轻型试验）中的作用，通过抑制脑内普萘洛尔（基于机理型抑制剂）和用尼古丁诱导脑CYP2D诱导脑CYP2D。抑制脑CYP2D的脑CYP2D增加血小录（1.8倍; P <0.03）和镇痛（1.5倍AUC（0-60）; P <0.001），同时诱导脑CYP2D增加脑杂志水平（4.6倍; P <0.001）和镇痛减少（0.8倍; P <0.02）。抑制诱导的脑CYP2D反转羟考酮水平的变化（1.2倍; p＆ 0.1）和镇痛（1.1倍; p＆ 0.3）。脑，但不是血浆，代谢比受到预处理的影响。峰镇痛与离体大脑相反（P <0.003），但不是肝（P＆GT; 0.9），CYP2D活性。改变脑CYP2D没有影响来自口服xymorphone的镇痛（P＆ 0.9用于跨所有组的AUC（0-60）），这不是CYP2D衬底。因此，脑CYP2D代谢改变了局部羟考酮水平和反应，表明脑CYP2D活性增加的人可能会降低羟考酮反应。改变个体羟考酮反应的因素可用于优化治疗和最小化滥用责任。

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