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

描述（由申请人提供）：近年来，处方阿片类镇痛药的非法滥用呈上升趋势。这种非法使用与阿片激动剂的奖励/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，加上非麻醉性镇痛剂，如对乙酰氨基酚。尽管组合镇痛制剂在治疗疼痛方面是有效的，但与单独的阿片样物质激动剂相比，组合制剂是否具有更大的奖励性质尚不清楚，这可能导致更多的使用和滥用。已知对乙酰氨基酚不含奖励作用;然而，当与阿片类激动剂（如氢可酮）联合使用时，它可能会增强其奖励特性。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。特别地，对乙酰氨基酚被代谢成AM404，已知AM404是内源性大麻素anandamide的转运体阻断剂，以及瞬时受体电位香草素1型（TRPV 1）受体的激动剂。因此，我们假设对乙酰氨基酚将通过这种新的机制增强/增强氢可酮在大鼠中的奖励特性。因此，在一系列的实验中，我们建议解决对乙酰氨基酚是否能够提高氢可酮的奖励性质使用条件性位置偏好范例。我们还将讨论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形成来阻断。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CB 1或TRPV 1受体的拮抗作用来阻断。由这个资助机会提供的资金可以促进和补充我们目前的启动研究资金，已经由药学院在健康科学的西部大学提供。 公共卫生相关性：在过去十年中，美国处方类阿片镇痛剂的非医疗（非法）使用显著增加。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（商业上称为Vicodin（R））的处方阿片类镇痛药是否具有比单独药物更大的奖励作用。该项目的研究结果将揭示药物（如维柯丁）的滥用倾向，并将促进我们对非法使用和滥用处方阿片类镇痛药物增加的原因的理解。

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.