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.

项目总结/摘要 医生们以前被告知，对疼痛治疗不足是医疗事故，现在他们被告知， 必须尽可能避免开阿片类药物，因为有成瘾的风险。然而，虽然止痛药 如非甾体类抗炎药在缓解轻度疼痛方面是有效的，但它们几乎不能提供 缓解阿片类药物所能缓解的剧烈疼痛。我们最近的工作表明，可能有可能获得有效的缓解， 使用阿片类药物可缓解剧烈疼痛，成瘾风险大大降低。 在2018年，我们报告说，人类海洛因成瘾者的大脑中， “可检测的”下丘脑泌素（Hcrt=食欲素）神经元和这些神经元的22%萎缩[1]。我们发现 这些变化可以持续超过药物摄入至少3年。我们进一步报道了Hcrt的类似变化， 神经元的数量和大小可以通过长期每天给予成瘾剂量的吗啡来诱导， 小鼠我们发现这些变化不是神经发生的结果，而是Hcrt增加的结果。 在基线时，“Hcrt神经元”中的Hcrt合成不产生可检测量的Hcrt肽。随后，委员会注意到， 阿斯顿-琼斯的研究小组报告说，可卡因和可卡因中可检测到的Hcrt神经元数量也有类似的增加。 芬太尼成瘾大鼠，表明这是一个相关的几种类型的成瘾。我们在2000年报道过 平均90%的Hcrt神经元的丧失是人类嗜睡症的原因[2，3]。发作性 人类药物滥用率极低，尽管他们每天都按处方使用成瘾药物， 这与Hcrt在成瘾中的重要作用一致。我们发现，吗啡治疗的“发作性睡眠”小鼠， Hcrt神经元已经被选择性地消融，极大地减少了纳洛酮触发的厌恶，即 “不那么上瘾”最近，我们报告说，长期阿片类药物管理大大增加了预测， Hcrt神经元到蓝斑[4]和腹侧被盖区（图5），这些区域与成瘾有关。 我们现在发现，成瘾相关的行为变化以及Hcrt神经元的数量和大小 由吗啡在小鼠中产生的Hcrt受体的双重拮抗剂苏沃雷生完全阻止。 我们的初步数据表明，吗啡的镇痛作用不会被苏沃雷生减弱。我们将 比较苏沃雷生与Hcrt-R1和Hcrt-R2拮抗剂在减少阿片诱导的 Hcrt神经元的变化，并减少阿片类药物的预期和纳洛酮诱导的厌恶。我们将 确定Hcrt-R1或Hcrt-R2阻断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神经元活性和阿片诱导的Hcrt轴突增加的影响 预测，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，用阿片类药物缓解严重疼痛可能很快就会成为可能。 而不会导致阿片类药物成瘾，从而减少美国阿片类药物死亡人数，目前每年超过76，000人。