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Variable brain oxycodone metabolism alters drug effect

可变的脑羟考酮代谢改变药物作用

基本信息

批准号：
10453716
负责人：
RACHEL Fynvola TYNDALE
金额：
$ 28.95万
依托单位：
UNIVERSITY OF TORONTO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10453716
关键词：
Absence of pain sensation Affect Analgesics Animals Blood Brain CYP3A4 gene Cerebral Ventricles Chemicals Chronic Codeine Consumption Crime Cytochrome P450 Data Dependence Dopamine Dopamine Receptor Dose Drug Addiction Drug Kinetics Drug Modelings Emergency department visit Enzymes Foundations Gender Genetic Health Care Costs Hepatic Human Hydrocodone Individual Knowledge Lead Liver Measures Metabolic Metabolic Activation Metabolism Methods Microdialysis Modeling Morphine Neurotransmitters Nicotine Opiate Addiction Opioid Opioid Analgesics Opioid Receptor Opioid agonist Oral Oxycodone Oxymorphone Pain management Parents Persons Pharmaceutical Preparations Plasma Play Positron-Emission Tomography Productivity Rattus Reporting Research Methodology Rewards Risk Role Sex Differences Smoker Smoking Source Techniques Testing Time Tramadol Treatment Failure Variant Woman abuse liability addiction brain metabolism brain pathway conditioned place preference drug misuse drug reward environmental chemical experience high reward high risk human model imaging study improved inhibitor inter-individual variation liver function mu opioid receptors nicotine patch nicotine treatment non-smoker novel opiate tolerance opioid abuse opioid exposure opioid user overdose death pain relief pharmacodynamic model pharmacokinetic model preclinical study receptor binding response sex societal costs translational study virtual

项目摘要

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.

7. 项目总结/文摘

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Sex, estrous cycle, and hormone regulation of CYP2D in the brain alters oxycodone metabolism and analgesia.

DOI：
10.1016/j.bcp.2022.114949
发表时间：
2022-04
期刊：
BIOCHEMICAL PHARMACOLOGY
影响因子：
5.8
作者：
Arguelles, Nicole;Richards, Janielle;El-Sherbeni, Ahmed A.;Miksys, Sharon;Tyndale, Rachel F.
通讯作者：
Tyndale, Rachel F.

Sex and Estrous Cycle Differences in Analgesia and Brain Oxycodone Levels.