Deterrents for prescription opioid abuse

处方阿片类药物滥用的威慑因素

基本信息

批准号：
10616752
负责人：
Kevin B. Freeman
金额：
$ 54.82万
依托单位：
UNIVERSITY OF MISSISSIPPI MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-15 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10616752
关键词：
Absence of pain sensation Acute Pain Address Adopted Adverse effects Agonist Analgesics Animal Model Azoles Behavior Behavioral Characteristics Clinical Constipation Data Depressed mood Development Diuresis Dose Drug Combinations Epidemic Exhibits Food Formulation Future GTP-Binding Proteins Goals Laboratories Macaca mulatta Measures Mediating Modality Nausea Opioid Opioid Analgesics Opioid agonist Outcome Outcome Measure Overdose Oxycodone Pain Pain management Pathway interactions Pharmaceutical Preparations Pharmacology Phase Procedures Public Health Rattus Reinforcement Schedule Reporting Risk Sedation procedure Self Administration Series Signal Transduction Signaling Protein Specialist Techniques Testing Therapeutic Treatment Efficacy Visceral pain Whole Body Plethysmography Work abuse liability antinociception behavioral outcome drug discovery effective therapy inflammatory pain kappa opioid receptors mu opioid receptors novel opioid epidemic pain model pain outcome painful neuropathy pharmacologic prescription opioid prescription opioid abuse programs respiratory sedative side effect therapeutic development

项目摘要

Project Summary Mu opioid receptor (MOR) agonists are the most effective treatments for moderate to severe acute pain, but their high abuse liability and risk for lethal overdose have exacted a significant toll on public health in recent years. Our program of study has investigated the feasibility of combining MOR agonists with kappa opioid receptor (KOR) agonists to deter abuse and enhance pain-decreasing effects. Our findings from Project Period 1 of this program indicate that the atypical KOR agonist, nalfurafine, decreases oxycodone’s abuse-related effects and enhances analgesia, but nalfurafine also produced significant sedative effects on its own. Recently, new KOR agonists have been developed that are reported to produce even fewer of the adverse behavioral effects that are typical of the KOR-agonist class. These atypical KOR agonists have been described as “G-protein biased” due to their greater potency to activate G-protein signaling relative to other pathways at the KOR. Our preliminary data indicate that the biased KOR agonist, triazole 1.1, is more therapeutically selective than nalfurafine. However, it is unknown if the positive characteristics observed with triazole 1.1 are due to G-protein bias or other potential mechanisms peculiar to the structural class. The overall goal of this renewal application is to systematically investigate combinations of oxycodone with new atypical KOR agonists that are reported to be G-protein biased from different structural classes to determine if reported signaling bias is associated with increased therapeutic selectivity (decreased abuse potential; enhanced antinociception) and reduced KOR-mediated “side effects”. To accomplish this goal, we will use complementary animal models (rhesus monkeys and rats) and rigorous quantitative pharmacology to determine if the atypical KOR agonists can reduce oxycodone’s abuse- related effects (Specific Aim 1), augment oxycodone’s pain-decreasing effects (Aim 2), and produce fewer side effects when combined with oxycodone (Aim 3). We will relate the relative potencies of the various KOR agonists to produce therapeutic and unwanted side effects to identify optimal leads for future development of therapeutics that activate MORs and KORs (dual-acting molecules; drug combinations). The studies proposed in this renewal will positively impact public health by laying the groundwork for the development of non-addictive pain medications that will retain the high treatment efficacy of current prescription opioids.

项目摘要 Mu Opioid受体（MOR）激动剂是中度至重度急性的最有效的治疗方法痛苦，但他们的高虐待责任和致命过量的风险给公众带来了重大损失近年来健康。我们的研究计划调查了合并MOR的可行性患有Kappa阿片受体（KOR）激动剂的激动剂来确定滥用并增强疼痛缓解效果。我们从本计划的项目1开始的发现，表明非典型的Kor Agonist， Nalfurafine，减少了羟考酮与滥用相关的效果并增强镇痛，但纳尔富拉芬还产生了重大的镇静作用。最近，新的kor激动剂已经据报道，开发的产生典型的不良行为效应的较少 kor-and-andist阶级。这些非典型的Kor激动剂被描述为“ G蛋白有偏见” 由于它们具有更大的效力，可以激活G蛋白信号相对于Kor的其他途径。我们的初步数据表明偏见的kor激动剂三唑1.1更热选择性比纳尔富芬。但是，尚不清楚三唑1.1观察到的阳性特征是由于G蛋白偏差或结构类别特有的其他潜在机制。总体目标这种更新的应用是系统地研究羟考酮与新的组合据报道是从不同的结构类别偏向G蛋白的非典型Kor激动剂确定报告的信号偏置是否与治疗选择性提高有关（降低）滥用潜力；增强的抗伤害感受）并减少了Kor介导的“副作用”。完成这个目标，我们将使用完整的动物模型（恒河猴和大鼠）和严格定量药理学来确定非典型的kor激动剂是否可以减少氧气滥用的氧气 - 相关效果（特定目标1），增强羟考酮的止痛效果（AIM 2），并产生与羟考酮混合使用时较少的副作用（AIM 3）。我们将联系各种Kor激动剂产生理论和不必要的副作用，以识别最佳潜在客户激活MOR和KOR的理论的未来发展（双作用分子；药物组合）。此次续签提出的研究将通过建立开发非成瘾性止痛药的基础，该药物将保留高度治疗当前处方OOID的功效。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The G-protein biased mu-opioid agonist, TRV130, produces reinforcing and antinociceptive effects that are comparable to oxycodone in rats.

DOI：
10.1016/j.drugalcdep.2018.08.002
发表时间：
2018-11-01
期刊：
Drug and alcohol dependence
影响因子：
4.2
作者：
Austin Zamarripa C;Edwards SR;Qureshi HN;Yi JN;Blough BE;Freeman KB
通讯作者：
Freeman KB

The kappa-opioid receptor agonist, triazole 1.1, reduces oxycodone self-administration and enhances oxycodone-induced thermal antinociception in male rats.

DOI：
10.1007/s00213-021-05965-x
发表时间：
2021-12
期刊：
Psychopharmacology
影响因子：
3.4
作者：
Zamarripa CA;Pareek T;Schrock HM;Prisinzano TE;Blough BE;Sufka KJ;Freeman KB
通讯作者：
Freeman KB

Comparison of cocaine reinforcement in lean and obese Zucker rats: Relative potency and reinstatement of extinguished operant responding.

瘦和肥胖 Zucker 大鼠中可卡因强化的比较：相对效力和熄灭的操作反应的恢复。

DOI：
10.1016/j.physbeh.2016.12.016
发表时间：
2017
期刊：
Physiology & behavior
影响因子：
2.9
作者：
Townsend,EAndrew;Freeman,KevinB
通讯作者：
Freeman,KevinB

Pharmacotherapies for decreasing maladaptive choice in drug addiction: Targeting the behavior and the drug.

DOI：
10.1016/j.pbb.2017.06.015
发表时间：
2018-01
期刊：
Pharmacology, biochemistry, and behavior
影响因子：
0
作者：
Perkins FN;Freeman KB
通讯作者：
Freeman KB

The kappa-opioid receptor agonist, nalfurafine, blocks acquisition of oxycodone self-administration and oxycodone's conditioned rewarding effects in male rats.

DOI：
10.1097/fbp.0000000000000581
发表时间：
2020-12
期刊：
Behavioural pharmacology
影响因子：
1.6
作者：
Zamarripa CA;Patel TR;Williams BC;Pareek T;Schrock HM;Prisinzano TE;Freeman KB
通讯作者：
Freeman KB