Characterization of delta/mu opioid receptor interactions on chronic osteoarthrit

慢性骨关节炎 delta/mu 阿片受体相互作用的表征

• 批准号: 8687870
• 负责人: Glenn W. Stevenson
• 金额: $ 36.66万
• 依托单位: UNIVERSITY OF NEW ENGLAND
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8687870
• 关键词: Absence of pain sensation; Acute; Acute Pain; Adaptive Behaviors; Address; Adverse effects; Agonist; Analgesics; Anti-Inflammatory Agents; Anti-inflammatory; Aspirin; Attenuated; Behavior; Behavioral; Biological Assay; Bone Density; Cardiovascular Physiology; Chemicals; Chronic; Chronic Disease; Clinical; Clinical Medicine; Degenerative polyarthritis; Depressed mood; Development; Drug Combinations; Effectiveness; Environment; Exercise; Food; Fracture; Funding; Goals; Grant; Human; Imaging technology; Incidence; Iodoacetates; Joints; Laboratories; Locomotion; Measures; Medicine; Mental Depression; Methadone; Modeling; Motor; Musculoskeletal; New England; Opioid; Opioid Analgesics; Outcome; Outcome Measure; Oxycodone; Pain; Parents; Participant; Pathology; Pharmaceutical Preparations; Pre-Clinical Model; Rattus; Relative (related person); Reporting; Respiratory physiology; Rodent; Running; Sedation procedure; Testing; Therapeutic; Therapeutic Effect; Time; Treatment Effectiveness; Treatment Efficacy; Universities; Ventilatory Depression; Withdrawal; base; bone; chronic pain; delta opioid receptor; drug development; feeding; gastrointestinal function; immune function; in vivo imaging; motor impairment; mu opioid receptors; nonhuman primate; novel; pain behavior; parent grant; pre-clinical; pre-clinical research; prescription opioid; public health relevance; research clinical testing; research study; response; restoration; screening; treatment effect; undergraduate research

DESCRIPTION (provided by applicant): Prescription opioid analgesics are among the frontline treatments for chronic pain. However, inconsistent therapeutic effects and side effects limit their use. Thus, there is a dire need for more effective and safer analgesic drugs to treat chronic pain conditions. One effective strategy for opioid analgesic drug development is to exploit interactions between delta and mu opioid receptors, using fixed-ratio mixtures of delta and mu agonists, with the goal of creating an optimum mixture that produces synergistic analgesic effects but only additive or sub-additive side effects. Drug combinations are common in medicine (e.g., oxycodone + aspirin), and experimental evidence indicates that combinations of delta and mu opioids produce enhanced analgesia with attenuated side effects, such as respiratory depression and sedation. Given that recent clinical and preclinical reports indicate that mu opioids produce bone/joint pathology, this class of compounds may be especially dangerous to prescribe for musculoskeletal chronic pain conditions. The main goal of this renewal is to evaluate delta/mu interactions on antinociceptive and bone/joint pathology outcomes. The primary hypothesis is that delta/mu agonist mixtures will produce synergistic antinociception but only additive or sub- additive bone/joint pathology. Of course, the assessment of these delta/mu opioid combinations requires predictive and reliable preclinical assays of pain. Although pain is typically associated with pain-stimulated behaviors (e.g., withdrawal responses) and pain-depressed behaviors (e.g., decreases in normally adaptive behaviors like feeding, locomotion, exercise), current preclinical measures of pain rely almost exclusively on pain-stimulated behaviors. This approach has several limitations: First, although assays of pain-stimulated behaviors are predictive of acute pain states, they do not parallel the topography of chronic pain behaviors. Second, assessment of chronic pain in clinical medicine relies heavily on quantification of pain-depressed behavior to assess the presence and impact of pain, and effectiveness of treatment. Finally, drugs may decrease pain-stimulated behaviors by producing motor impairment, which results in a "false positive" treatment effect. During the parent R15 grant cycle, my laboratory developed several assays of acute and chronic pain-depressed behaviors using feeding, locomotion, wheel running and operant responding as endpoints, and we developed an assay of osteoarthritis pain-depressed wheel running in rats. I will extend the findings of the parent grant according to 2 specific aims: (1) Evaluate delta/mu agonist interactions in assays of osteoarthritis pain-depressed wheel running and operant responding, and (2) Utilize in vivo imaging to evaluate delta/mu agonist interactions on bone/joint pathology in rats with/without osteoarthritis, and with/without access to running wheels. Successful completion of these experiments will facilitate discovery of delta/mu mixtures that produce enhanced pain relief with reduced bone pathology. A favorable preclinical therapeutic/side effect profile of delta/mu combinations may indicate that clinical testing in human participants is warranted.

描述（由申请人提供）：处方阿片类镇痛药是慢性疼痛的一线治疗方法。但是，不一致的治疗作用和副作用限制了它们 使用。因此，迫切需要更有效，更安全的镇痛药来治疗慢性疼痛状况。阿片类镇痛药物开发的一种有效策略是利用三角洲和MU激动剂的固定比例混合物来利用三角洲和MU阿片受体之间的相互作用，目的是创建一种最佳混合物，从而产生协同的镇痛作用，但仅产生添加剂或亚辅助副作用。药物组合在医学中很常见（例如羟考酮 +阿司匹林），实验证据表明，三角洲和阿片类药物的组合产生增强的镇痛作用，并具有减弱的副作用，例如呼吸道抑郁和镇静。鉴于最近的临床和临床前报告表明，MU阿片类药物会产生骨/关节病理，因此为肌肉骨骼骨骼慢性疼痛疾病开处方可能特别危险。这种更新的主要目的是评估抗伤害感受和骨/关节病理结果的Delta/MU相互作用。主要的假设是，三角/MU激动剂混合物将产生协同的抗伤害感受，而仅产生添加剂或亚添加性骨/关节病理学。当然，对这些三角洲/MU阿片类药物组合的评估需要疼痛的预测性和可靠的临床前分析。尽管疼痛通常与疼痛刺激的行为（例如，戒断反应）和疼痛抑郁的行为有关（例如，诸如喂养，运动，运动，运动）的正常适应性行为的减少几乎完全依赖于疼痛刺激的行为。这种方法有几个局限性：首先，尽管对疼痛刺激的行为的测定是预测急性疼痛态的，但它们与慢性疼痛行为的地形没有平行。其次，临床医学中慢性疼痛的评估在很大程度上依赖于对疼痛抑郁行为的量化，以评估疼痛的存在和影响以及治疗的有效性。最后，药物可以通过产生运动障碍来减少疼痛刺激的行为，从而导致“假阳性”治疗效果。在父级R15赠款周期期间，我的实验室使用喂养，运动，车轮跑步和操作者作为终点进行了几种急性和慢性疼痛抑郁的行为，我们开发了骨关节炎止痛的轮子在大鼠中延伸的抑制轮。 I will extend the findings of the parent grant according to 2 specific aims: (1) Evaluate delta/mu agonist interactions in assays of osteoarthritis pain-depressed wheel running and operant responding, and (2) Utilize in vivo imaging to evaluate delta/mu agonist interactions on bone/joint pathology in rats with/without osteoarthritis, and with/without access to running wheels.这些实验的成功完成将有助于发现三角/MU混合物，从而通过减少骨骼病理来增加疼痛缓解疼痛。 Delta/MU组合的有利的临床前治疗/副作用可能表明，有必要进行人类参与者的临床测试。

项目成果

The mixed-action delta/mu opioid agonist MMP-2200 does not produce conditioned place preference but does maintain drug self-administration in rats, and induces in vitro markers of tolerance and dependence.

• DOI: 10.1016/j.pbb.2015.02.022
• 发表时间: 2015-05
• 期刊: Pharmacology, biochemistry, and behavior
• 作者: Stevenson GW;Luginbuhl A;Dunbar C;LaVigne J;Dutra J;Atherton P;Bell B;Cone K;Giuvelis D;Polt R;Streicher JM;Bilsky EJ
• 通讯作者: Bilsky EJ