Deterrents for prescription opioid abuse

处方阿片类药物滥用的威慑因素

• 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
• 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

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.

项目概要 Mu阿片受体（MOR）激动剂是中度至重度急性发作最有效的治疗方法 痛苦，但它们的高滥用倾向和致命过量的风险给公众造成了重大损失 近年来，我们的研究计划调查了结合 MOR 的可行性。 激动剂与 kappa 阿片受体 (KOR) 激动剂可防止滥用并增强镇痛效果 我们在该计划第 1 阶段的研究结果表明，非典型 KOR 激动剂， 纳芙拉芬，减少羟考酮的滥用相关作用并增强镇痛作用，但纳芙拉芬 最近，新的 KOR 激动剂也产生了显着的镇静作用。 据报道，已开发出更少的典型不良行为影响 这些非典型 KOR 激动剂被描述为“G 蛋白偏向”。 由于它们相对于 KOR 的其他途径激活 G 蛋白信号传导的能力更强。 初步数据表明偏向的 KOR 激动剂三唑 1.1 更具治疗选择性 然而，尚不清楚三唑 1.1 观察到的积极特征是否有效。 由于 G 蛋白偏差或结构类别的其他潜在特性。 该更新申请的目的是系统地研究羟考酮与新药物的组合 据报道，非典型 KOR 激动剂的 G 蛋白偏向于不同的结构类别 确定报告的信号偏倚是否与治疗选择性增加（减少 滥用潜力；增强抗伤害作用）并减少 KOR 介导的“副作用”。 为了这个目标，我们将使用互补的动物模型（恒河猴和大鼠）和严格的 定量药理学以确定非典型 KOR 激动剂是否可以减少羟考酮的滥用 相关作用（具体目标 1），增强羟考酮的减轻疼痛作用（目标 2），并产生 与羟考酮联合使用时副作用更少（目标 3）。 各种 KOR 激动剂产生治疗作用和不良副作用，以确定最佳引线 激活 MOR 和 KOR（双作用分子；药物）的疗法的未来发展 本次更新中提出的研究将通过奠定以下基础对公共健康产生积极影响。 为开发非成瘾性止痛药物奠定基础，以保持高治疗效果 当前处方阿片类药物的功效。

项目成果

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。

• 发表时间: 2017-03-01
• 影响因子: 2.9
• 作者: Townsend, E Andrew;Freeman, Kevin B
• 通讯作者: Freeman, Kevin B

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

kappa-阿片受体激动剂三唑 1.1 可减少雄性大鼠羟考酮的自我给药并增强羟考酮诱导的热镇痛作用。

• 发表时间: 2021-12
• 影响因子: 3.4
• 作者: Zamarripa, C Austin;Pareek, Tanya;Schrock, Hayley M;Prisinzano, Thomas E;Blough, Bruce E;Sufka, Kenneth J;Freeman, Kevin B
• 通讯作者: Freeman, Kevin B

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

kappa-阿片受体激动剂纳芙拉芬可阻止雄性大鼠获得羟考酮自我给药和羟考酮的条件性奖赏效应。

• 发表时间: 2020
• 影响因子: 1.6
• 作者: Zamarripa, C Austin;Patel, Tilak R;Williams, B Cole;Pareek, Tanya;Schrock, Hayley M;Prisinzano, Thomas E;Freeman, Kevin B
• 通讯作者: Freeman, Kevin B

Shallow discounting of delayed cocaine by male rhesus monkeys when immediate food is the choice alternative.

当直接食物是选择时，雄性恒河猴对延迟可卡因的使用会小幅折扣。

• 发表时间: 2016-12
• 影响因子: 2.3
• 作者: Huskinson, Sally L;Myerson, Joel;Green, Leonard;Rowlett, James K;Woolverton, William L;Freeman, Kevin B
• 通讯作者: Freeman, Kevin B

Abuse Potential of Biased Mu Opioid Receptor Agonists.

偏向 Mu 阿片受体激动剂的滥用潜力。

• 发表时间: 2018
• 影响因子: 13.8
• 作者: Negus, S Stevens;Freeman, Kevin B
• 通讯作者: Freeman, Kevin B