Variable brain oxycodone metabolism alters drug effect

7.项目总结/摘要 阿片类药物是有效的止痛药，通过作用于大脑的μ-阿片受体， 同时激活奖励大脑通路，这可能导致阿片类药物耐受和药物依赖。 美国是世界上人均使用阿片类药物最多的国家，造成了巨大的健康和社会成本。 与成瘾和治疗、生产力下降和犯罪增加有关。对阿片类药物的反应各不相同 广泛存在于人与人之间，也可能存在于性别之间，但目前尚不清楚为什么人们的经历不同 相同阿片类药物的疼痛缓解水平，以及为什么有些人会上瘾。许多阿片类药物 被CYP 2D酶激活为更有效的μ-阿片受体激动剂，如羟考酮， 转化为羟吗啡酮然而，羟吗啡酮比羟吗啡酮更快地被运输出大脑和身体。 羟考酮，因此羟考酮负责镇痛。该项目采用独特的研究方法， 研究脑内CYP 2D酶代谢阿片类药物在羟考酮、曲马多中的重要性 和氢可酮反应。肝脏和大脑CYP 2D水平均受遗传学调节，但除此之外， CYP 2D对环境化学物质非常敏感，尤其是尼古丁。因此，可以有两个人 在肝脏中具有相同的CYP 2D活性（相同的遗传学），但在肝脏中具有非常不同的CYP 2D活性水平。 大脑，例如通过吸烟。他们的药物和代谢物的血液水平可能是相似的，但代谢， 脑CYP 2D可以改变脑中羟考酮的水平，影响疼痛缓解、耐受性和滥用倾向。 “脑中CYP 2D引起的羟考酮代谢变化如何影响羟考酮镇痛， 奖励？”镇痛、耐受和奖赏的经验证大鼠模型将与药物和多巴胺一起使用 微透析、药代动力学建模和已建立的操纵脑而非肝CYP 2D的方法 程度.脑内注射化学抑制剂会降低脑内CYP 2D，而慢性注射则会增加脑内CYP 2D。 全身尼古丁治疗。降低脑CYP 2D应增加镇痛，耐受性和奖励，通过 减少羟考酮转化为羟吗啡酮，导致脑羟考酮水平升高。增加的脑 CYP 2D应通过羟考酮的更大代谢降低镇痛、耐受和奖赏， 羟吗啡酮，导致大脑羟考酮水平降低。血浆羟考酮和代谢物水平不会 因为肝脏CYP 2D不受这些操作的影响。两种额外的CYP 2D底物，通常 处方的口服阿片类药物，氢可酮和曲马多，以及羟考酮反应的性别差异也将被 研究了这将提高对人与人之间这种新的变异来源的机械理解， 他们的阿片类药物反应，并确定个人在阿片类药物治疗失败的风险和进展， 依赖于这些广泛使用的口服阿片类药物。广泛的PB-PK建模将有助于外推 人类，正如计划的人类PET成像研究一样。从这个项目中获得的知识将有助于 我们正在努力减少阿片类药物滥用和依赖的社会和健康成本。

7. Project Summary/Abstract Opioid drugs are effective pain-relievers that elicit analgesia through their action at brain µ-opioid receptors, simultaneously activating rewarding brain pathways, which can lead to opioid tolerance and drug dependence. The U.S. has the highest world-wide per capita use of opioids creating enormous health and societal costs related to addiction and treatment, lost productivity, and increased crime. Response to opioid drugs varies widely between people, and potentially between genders, but it is not clear why people experience different levels of pain relief from the same opioid, and why some people progress to become addicted. Many opioids are activated to even more potent µ-opioid receptor agonists by CYP2D enzymes, such as oxycodone that is converted to oxymorphone. However, oxymorphone is transported out of the brain and body more rapidly than oxycodone, hence oxycodone is responsible for analgesia. This project uses unique research methods to investigate how metabolism of opioids by CYP2D enzymes in the brain is important in oxycodone, tramadol and hydrocodone response. Both liver and brain CYP2D levels are regulated by genetics, but in addition, brain CYP2D is very sensitive to environmental chemicals, notably nicotine. Therefore, there can be two individuals who have the same CYP2D activity in the liver (same genetics) but very different levels of CYP2D activity in the brain, e.g. through smoking. Their drug and metabolite blood levels may be similar, but metabolism by brain CYP2D can alter oxycodone levels in the brain, influencing pain relief, tolerance and abuse liability. “How does variation in oxycodone metabolism by CYP2D in the brain affect oxycodone analgesia and reward?” Validated rat models of analgesia, tolerance and reward, will be used with drug and dopamine microdialysis, pharmacokinetic modelling, and established methods of manipulating brain but not liver CYP2D levels. Brain CYP2D will be reduced by injecting chemical inhibitors into the brain, and increased by chronic systemic nicotine treatment. Decreased brain CYP2D should increase analgesia, tolerance and reward through reduced oxycodone conversion to oxymorphone, resulting in higher brain oxycodone levels. Increased brain CYP2D should decrease analgesia, tolerance and reward through greater metabolism of oxycodone to oxymorphone, resulting in lower brain oxycodone levels. Plasma oxycodone and metabolites levels will not change as liver CYP2D is unaffected by these manipulations. Two additional CYP2D substrates, the commonly prescribed oral opioids, hydrocodone and tramadol, and sex differences in oxycodone responses will also be investigated. This will improve mechanistic understanding of this novel source of variation between people in their opioid response, and identification of individuals at risk for opioid pain-treatment failure and progression to dependence on these widely used oral opioids. Extensive PB-PK modelling will assist in extrapolations to human, as will planned human PET imaging studies. The knowledge acquired from this project will contribute to our on-going efforts to reduce the societal and health costs of opioid drug misuse and dependence.