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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要医生们以前被告知对疼痛治疗不足是医疗事故，现在却被告知他们必须尽可能避免开阿片类药物，因为存在成瘾风险。例如非甾体抗炎药可以有效缓解轻度疼痛，但它们几乎不能提供我们最近的研究表明，阿片类药物可以有效缓解剧烈疼痛。阿片类药物引起剧烈疼痛，成瘾风险大大降低。 2018 年，我们报告称，人类海洛因成瘾者大脑中的数量平均增加了 54% 我们发现，“可检测到的”下丘脑分泌素 (Hcrt=orexin) 神经元的数量减少了 22%[1]。我们进一步报道了 Hcrt 的类似变化。长期每日给予成瘾剂量的吗啡可以诱导神经元的数量和大小我们证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”中的合成在基线时未产生可检测量的 Hcrt 肽。阿斯顿-琼斯小组报告称，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。芬太尼成瘾的老鼠，表明这与我们在 2000 年报道的几种类型的成瘾有关。平均 90% 的 Hcrt 神经元丧失是人类发作性睡病的原因 [2,3]。人类的药物滥用率极低，尽管他们每天都按规定使用成瘾药物，我们发现吗啡治疗“发作性睡病”小鼠，这与 Hcrt 在成瘾中的重要作用一致。 Hcrt 神经元已被选择性消融，大大减少了纳洛酮引发的厌恶，即 “减少成瘾。”最近我们报道说，长期服用阿片类药物大大增加了对阿片类药物的预测。 Hcrt 神经元连接到蓝斑 [4] 和腹侧被盖区（图 5），这些区域与成瘾相关。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 Hcrt 受体拮抗剂 suvorexant 可以完全阻止小鼠体内吗啡产生的作用。我们的试验数据表明，suvorexant 不会减弱吗啡的镇痛作用。比较 suvorexant 与 Hcrt-R1 和 Hcrt-R2 拮抗剂在减少阿片类药物诱导方面的有效性 Hcrt 神经元的变化，以及减少阿片类药物预期和纳洛酮引起的厌恶。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 神经元活性和阿片类药物诱导的 Hcrt 轴突增加的影响使用定量共聚焦显微镜进行预测，单位活动和体内钙的电记录我们的试验数据表明，阿片类药物可能很快就能缓解严重疼痛。不会引起阿片类药物成瘾，从而减少美国阿片类药物导致的死亡人数，目前美国每年有超过 76,000 人死亡。