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

描述（由申请人提供）：处方阿片类镇痛药的非法滥用近年来呈上升趋势。这种非法使用与阿片类激动剂的奖励/强化特性有关。然而，许多处方阿片类镇痛药含有两种化合物的组合：阿片类激动剂，如氢可酮，加上非麻醉性镇痛药，如对乙酰氨基酚。尽管联合镇痛制剂在治疗疼痛方面有效，但与单独使用阿片类激动剂相比，联合制剂是否具有更大的回报特性尚不清楚，这可能导致更多的使用和滥用。对乙酰氨基酚不知道含有奖励作用；然而，当阿片类激动剂（如氢可酮）联合使用时，它可能会增强其有益的特性。有趣的是，最近的研究结果表明，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成AM404，已知AM404是内源性大麻素anandamide的转运蛋白阻滞剂，也是瞬时受体电位香草样蛋白1 （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机制增强/增强氢可酮在大鼠中的奖励特性。因此，在一系列实验中，我们建议使用条件位置偏好范式来解决对乙酰氨基酚是否能够增强氢可酮的奖励特性。我们还将探讨对乙酰氨基酚对氢可酮奖赏的增强作用是否可以通过预防AM404的形成而被阻断。最后，我们将讨论对乙酰氨基酚对氢可酮奖赏的作用是否可以通过CB1或TRPV1受体的拮抗作用来阻断。这个资助机会提供的资金可以促进和补充我们目前由西部健康科学大学药学院提供的启动研究资金。

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.