The effects of acetaminophen on the rewarding properties of hydrocodone in rats

对乙酰氨基酚对大鼠氢可酮奖赏特性的影响

• 批准号: 7781129
• 负责人: Arbi Nazarian
• 金额: $ 3.75万
• 依托单位: WESTERN UNIVERSITY OF HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7781129
• 关键词: AM 251; AM404; Acetaminophen; Address; Agonist; Analgesics; Brain; CNR1 gene; Chemosensitization; Dose; Drug Formulations; Endocannabinoids; Enzymes; Funding; Funding Opportunities; Health Sciences; Hydrocodone; Hydrocodone/Acetaminophen; Individual; Injection of therapeutic agent; Laboratories; Lead; Light; Medical; Opioid; Opioid Analgesics; Pain; Pharmaceutical Preparations; Pharmacy facility; Prevention; Property; Protocols documentation; Rattus; Research; Rewards; Series; United States; Universities; Vanilloid; Vicodin; anandamide; base; capsazepine; college; conditioning; fatty acid amide hydrolase; inhibitor/antagonist; interest; non-opioid analgesic; novel; preference; prevent; public health relevance; receptor; research study

DESCRIPTION (provided by applicant): The illicit abuse of prescription opioid analgesics has been on the rise in recent years. This illicit use has been associated to the rewarding/reinforcing properties of opioid agonists. However, many prescription opioid analgesics contain a combination of two compounds: an opioid agonist, such as hydrocodone, plus a non-narcotic analgesic, such as acetaminophen. Although the combination analgesic formulations have been effective in treating pain, it is yet unknown whether the combined formulations possess greater rewarding properties, as compared to the opioid agonist alone, which may lead to greater use and abuse. Acetaminophen is not known to contain rewarding effects; however, it could possibly potentiate the rewarding properties of opioid agonists, such as hydrocodone, when combined. Interestingly, recent findings suggest that the analgesic actions of acetaminophen occur through its active metabolites. In particular, acetaminophen is metabolized into AM404, known to be a transporter blocker of the endocannabinoid anandamide, as well as an agonist for transient receptor potential vanilloid type 1 (TRPV1) receptors. We, therefore, hypothesize that acetaminophen will enhance/potentiate the rewarding properties of hydrocodone in rats through this novel mechanism. Therefore, in a series of experiments, we propose to address whether acetaminophen is able to enhance the rewarding properties of hydrocodone using the conditioned place preference paradigm. We will also address whether the enhancing effects of acetaminophen on hydrocodone reward can be blocked by prevention of AM404 formation. Lastly, we will address if the actions of acetaminophen on hydrocodone reward can be blocked by antagonism of CB1 or TRPV1 receptors. Funds provided by this funding opportunity can facilitate and supplement our current start-up research funds that have been provided by the College of Pharmacy at Western University of Health Sciences. PUBLIC HEALTH RELEVANCE: There has been a significant increase in the non-medical (illicit) use of prescription opioid analgesics in the United State over the past decade. Our project is set to determine whether prescription opioid analgesics that contain a combination of the two compounds, hydrocodone and acetaminophen (commercially known as Vicodin(R)), possess a greater rewarding effect than the individual drugs. The findings from this project will shed light on the abuse liability of drugs, such as Vicodin, and will advance our understanding as to why there has been an increase in the illicit use and abuse of prescription opioid analgesic drugs.

描述（由申请人提供）：近年来，非法滥用阿片类镇痛药的非法滥用一直在增加。这种非法用途与阿片类药物激动剂的奖励/增强特性有关。但是，许多处方阿片类镇痛药包含两种化合物的组合：阿片类药物激动剂，例如氢可酮，以及非麻醉镇痛药，例如乙酰氨基酚。尽管组合镇痛剂的配方在治疗疼痛方面有效，但与单独的阿片类药物激动剂相比，合并的配方是否具有更大的奖励性能，这可能会导致更多的使用和滥用。对乙酰氨基酚尚不包含奖励作用；但是，当组合时，它可能会增强阿片类药物激动剂（例如氢可酮）的奖励性能。有趣的是，最近的发现表明，对乙酰氨基酚的镇痛作用是通过其活性代谢物发生的。特别是，对乙酰氨基酚被代谢为AM404，已知是内源性大麻素anandamide的转运蛋白阻滞剂，以及用于瞬态受体电位Vanilloid 1型（TRPV1）受体的激动剂。因此，我们假设对乙酰氨基酚将通过这种新型机制增强/增强大鼠中氢可酮的奖励性能。因此，在一系列实验中，我们建议解决对乙酰氨基酚是否能够使用条件的位置偏好范式来增强氢可酮的奖励性能。我们还将解决对乙酰氨基酚对氢可酮奖励的增强作用是否可以通过预防AM404形成来阻止。最后，我们将解决对乙酰氨基酚对氢可酮奖励的作用，可以通过CB1或TRPV1受体的拮抗作用阻止。通过此资助机会提供的资金可以促进和补充西方卫生科学大学药学院提供的当前初创研究基金。 公共卫生相关性：在过去十年中，美国对处方阿片类镇痛药的非医学（非法）使用显着增加。我们的项目旨在确定含有两种化合物，氢可酮和对乙酰氨基酚（商业称为vicodin（R））的处方阿片类镇痛药是否具有比单个药物具有更大的奖励作用。该项目的发现将阐明诸如Vicodin之类的药物的滥用责任，并将促进我们对为什么非法使用和滥用处方阿片类镇痛药有所增加的理解。