Maintaining opioid analgesia and preventing addiction with hypocretin antagonism

通过下丘脑分泌素拮抗作用维持阿片类药物镇痛并预防成瘾

• 批准号: 10713175
• 负责人: JEROME M SIEGEL
• 金额: $ 56.2万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713175
• 关键词: Ablation; Absence of pain sensation; Action Potentials; Affect; Analgesics; Anatomy; Axon; Behavior; Brain; Cessation of life; Chronic; Cocaine; Confocal Microscopy; Data; Development; Dose; Drug abuse; Effectiveness; Epidemic; Fentanyl; Food; Heroin; Human; Intake; Laboratories; Link; Measures; Morphine; Mus; Naloxone; Narcolepsy; Neurons; Non-Steroidal Anti-Inflammatory Agents; Opiate Addiction; Opioid; Opioid Analgesics; Opioid Receptor; Pain; Pain management; Peptides; Pharmaceutical Preparations; Physicians; Rattus; Reporting; Risk; Role; Running; Secure; Shapes; Specificity; Substantia nigra structure; Substrate Interaction; Symptoms; Testing; Time; Tyrosine 3-Monooxygenase; Ventral Tegmental Area; Work; addiction; antagonist; compare effectiveness; hypocretin; in vivo calcium imaging; locus ceruleus structure; medical malpractice; morphine administration; nerve supply; neurogenesis; opioid mortality; opioid overdose; opioid use disorder; orexin A receptor; orexin B receptor; prescription opioid; preservation; prevent; receptor; response

Project Summary/Abstract Physicians, who were previously told that it is medical malpractice to undertreat pain, are now told that they must avoid prescribing opioids whenever possible because of the risk of addiction. However, while analgesics such as nonsteroidal anti-inflammatory drugs are effective in relieving mild pain, they do not provide nearly the relief of severe pain that opioids do. Our recent work suggests that it may be possible to secure potent relief for severe pain with opioids, with a greatly reduced risk of addiction. In 2018 we reported that the brains of human heroin addicts had an average 54% increase in the number of “detectable” hypocretin (Hcrt=orexin) neurons and a 22% shrinkage of these neurons[1]. We found that these changes can outlast drug intake for at least 3 years. We further reported that similar changes in Hcrt neuron number and size could be induced by longterm daily administration of addictive doses of morphine to mice. We showed that these changes were not a result of neurogenesis, rather resulting from increased Hcrt synthesis in “Hcrt neurons” not producing detectable amounts of the Hcrt peptides at baseline. Subsequently, Aston-Jones's group reported a similar increase in the number of detectable Hcrt neurons in cocaine and fentanyl addicted rats, indicating that this is a correlate of several types of addiction. We had reported in 2000 that the loss of, on average, 90% of Hcrt neurons was the cause of human narcolepsy [2,3]. Narcoleptic humans have an extremely low rate of drug abuse, despite their prescribed daily use of addictive drugs, consistent with an important role for Hcrt in addiction. We find that morphine treated “narcoleptic” mice, in which Hcrt neurons had been selectively ablated, have greatly reduced naloxone triggered aversion, i.e. are “less addicted.” Recently we reported that chronic opioid administration greatly increases the projections of Hcrt neurons to locus coeruleus [4] and to the ventral tegmental area (Fig 5), regions linked to addiction. We now find that the addiction-associated changes in behavior and in Hcrt neuron number and size produced by morphine in mice are completely prevented by the dual Hcrt receptor antagonist suvorexant. Our pilot data indicates that the analgesic effect of morphine is not diminished by suvorexant. We will compare the effectiveness of suvorexant with Hcrt-R1 and Hcrt-R2 antagonists in reducing opiate induced changes in Hcrt neurons, and in reducing opiate anticipation and naloxone induced aversion. We will determine if Hcrt-R1 or Hcrt-R2 blockers affect morphine analgesia. We will determine the effect of Hcrt antagonists on the activity of Hcrt neurons after morphine and on opioid induced increases in Hcrt axonal projections, using quantitative confocal microscopy, electrical recording of unit activity and in vivo calcium imaging of Hcrt neurons. Our pilot data suggest that it may soon be possible to relieve severe pain with opioids without causing opioid addiction, thereby reducing the US opioid death toll, which now exceeds 76,000/year.

项目摘要/摘要 医生以前被告知，低估疼痛是医疗事故，现在被告知，他们 必须尽可能避免开阿片类药物，因为有上瘾的风险。然而，虽然止痛药 如非类固醇消炎药对缓解轻微疼痛有效，它们不能提供接近 缓解阿片类药物的剧烈疼痛。我们最近的工作表明，有可能获得有效的缓解 阿片类药物带来的剧烈疼痛，大大降低了上瘾的风险。 在2018年，我们报告说，人类海洛因成瘾者的大脑数量平均增加了54% 可检测到的下丘脑神经元数(Hcrt=增食欲素)和这些神经元萎缩22%[1]。我们发现 这些变化可以持续至少3年。我们进一步报告了HCRT中类似的变化 长期每日给予成瘾剂量的吗啡可诱导神经元的数量和大小 老鼠。我们表明，这些变化不是神经发生的结果，而是Hcrt增加的结果。 “Hcrt神经元”的合成在基线时没有产生可检测到数量的Hcrt多肽。后来， Aston-Jones的研究小组报告说，可卡因中可检测到的Hcrt神经元的数量也有类似的增加 芬太尼成瘾的大鼠，表明这与几种类型的成瘾有关。我们在2000年曾报道过 平均90%的Hcrt神经元的丧失是人类发作性睡病的原因[2，3]。嗜睡症患者 人类的药物滥用比率非常低，尽管他们每天都会开出处方使用令人上瘾的药物， 与Hcrt在成瘾中的重要作用一致。我们发现吗啡治疗的“发作性睡病”小鼠， 其中Hcrt神经元已经被选择性地消融，大大减少了纳洛酮触发的厌恶，即 “没那么上瘾了。”最近我们报道，长期服用阿片类药物大大增加了对 Hcrt神经元连接到蓝斑[4]和腹侧被盖区(图5)，这两个区域与成瘾有关。 我们现在发现，与成瘾相关的行为以及Hcrt神经元数量和大小的变化 双重Hcrt受体拮抗剂suvorexant可完全阻止小鼠产生吗啡。 我们的初步数据表明，吗啡的止痛作用不会因苏醒而减弱。我们会 亚复氧与Hcrt-R1、Hcrt-R2拮抗剂减少阿片类药物诱导作用的比较 Hcrt神经元的变化，以及减少阿片类药物预期和纳洛酮诱导的厌恶。我们会 确定Hcrt-R1或Hcrt-R2阻滞剂是否影响吗啡镇痛。我们将确定HCRT的效果 拮抗剂对吗啡后Hcrt神经元活动的影响及阿片类药物引起Hcrt轴突的增加 投射，使用定量共聚焦显微镜，电记录单位活动和体内钙 Hcrt神经元的成像。我们的试验数据表明，阿片类药物可能很快就能缓解剧烈的疼痛。 而不会导致阿片成瘾，从而减少美国阿片类药物死亡人数，目前美国阿片类药物死亡人数超过每年76,000人。