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:
- 金额:$ 56.2万
- 依托单位:
- 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:
- 关键词:
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.
项目摘要/摘要
医师以前被告知这是治疗疼痛的医疗事故,现在被告知他们
由于有成瘾的风险,必须避免在可能的情况下开处方阿片类药物。但是,镇痛学
例如非甾体类抗炎药可有效缓解轻度疼痛,它们几乎没有提供
缓解阿片类药物的剧烈疼痛。我们最近的工作表明,有可能确保潜在的缓解
阿片类药物的严重疼痛,大大降低了成瘾的风险。
在2018年,我们报告说,人类海洛因成瘾者的大脑平均增加了54%
这些神经元的“可检测”低封素(HCRT = OREXIN)神经元和22%的收缩[1]。我们发现
这些变化至少可以超过摄入量至少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吗啡的长期给药
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”中的合成未在基线时产生可检测量的HCRT Pepperides。随后,
阿斯顿·琼斯(Aston-Jones)的小组报告说,可卡因和可卡因可检测的HCRT神经元数量也有类似的增加。
芬太尼添加了大鼠,表明这是几种类型的成瘾的相关性。我们在2000年报道了
平均90%的HCRT神经元的丧失是人类性疾病的原因[2,3]。麻醉剂
人类的药物滥用率极低,dospite是他们处方的日常使用添加剂,
与HCRT在成瘾中的重要作用一致。我们发现吗啡治疗了“麻醉剂”小鼠,
哪些HCRT神经元有选择性地消融,大大降低了纳洛酮的厌恶,即
“不那么上瘾。”最近我们报道,慢性阿片类药物管理大大增加了
HCRT神经元至层基因座[4]和腹侧对接区域(图5),与成瘾有关的区域。
现在,我们发现与成瘾相关的行为变化以及HCRT神经元数和大小
双重HCRT接收器拮抗剂Suvorexant完全阻止了吗啡产生的小鼠产生。
我们的试点数据表明,suvorexant不会减少吗啡的镇痛作用。我们将
比较Suvorexant与HCRT-R1和HCRT-R2拮抗剂在减少操作诱导的有效性
HCRT神经元的变化以及减少手术和纳洛酮引起的厌恶。我们将
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
吗啡后HCRT神经元的活性和阿片类药物诱导的HCRT轴突增加的拮抗剂
投影,使用定量共聚焦显微镜,单位活性的电记录和体内钙
HCRT神经元的成像。我们的飞行员数据表明,很快就有可能用阿片类药物来挽救严重的疼痛
而不会引起阿片类药物成瘾,从而减少了现在超过76,000/年的美国阿片类药物死亡人数。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

暂无数据
数据更新时间:2024-06-01
JEROME M SIEGEL的其他基金
Role of hypocretin in opiate addiction and withdrawal
下丘脑分泌素在阿片成瘾和戒断中的作用
- 批准号:1026896610268966
- 财政年份:2020
- 资助金额:$ 56.2万$ 56.2万
- 项目类别:
BLRD Senior Research Career Scientist Renewal Application
BLRD 高级研究职业科学家续签申请
- 批准号:1061825210618252
- 财政年份:2020
- 资助金额:$ 56.2万$ 56.2万
- 项目类别:
Role of hypocretin in opiate addiction and withdrawal
下丘脑分泌素在阿片成瘾和戒断中的作用
- 批准号:1064508710645087
- 财政年份:2020
- 资助金额:$ 56.2万$ 56.2万
- 项目类别:
Role of hypocretin in opiate addiction and withdrawal
下丘脑分泌素在阿片成瘾和戒断中的作用
- 批准号:98882609888260
- 财政年份:2020
- 资助金额:$ 56.2万$ 56.2万
- 项目类别:
BLRD Senior Research Career Scientist Renewal Application
BLRD 高级研究职业科学家续签申请
- 批准号:1045150210451502
- 财政年份:2020
- 资助金额:$ 56.2万$ 56.2万
- 项目类别:
Role of hypocretin in opiate addiction and withdrawal
下丘脑分泌素在阿片成瘾和戒断中的作用
- 批准号:1045575910455759
- 财政年份:2020
- 资助金额:$ 56.2万$ 56.2万
- 项目类别:
ShEEP Request for a Confocal Laser Scanning Microscope
ShEEP 请求共焦激光扫描显微镜
- 批准号:97958889795888
- 财政年份:2019
- 资助金额:$ 56.2万$ 56.2万
- 项目类别:
Environmental determinants of human sleep timing, duration and continuity: studies in hunter gatherers
人类睡眠时间、持续时间和连续性的环境决定因素:对狩猎采集者的研究
- 批准号:1044385510443855
- 财政年份:2019
- 资助金额:$ 56.2万$ 56.2万
- 项目类别:
Environmental determinants of human sleep timing, duration and continuity: studies in hunter gatherers
人类睡眠时间、持续时间和连续性的环境决定因素:对狩猎采集者的研究
- 批准号:1063316310633163
- 财政年份:2019
- 资助金额:$ 56.2万$ 56.2万
- 项目类别:
Environmental determinants of human sleep timing, duration and continuity: studies in hunter gatherers
人类睡眠时间、持续时间和连续性的环境决定因素:对狩猎采集者的研究
- 批准号:1024642410246424
- 财政年份:2019
- 资助金额:$ 56.2万$ 56.2万
- 项目类别:
相似海外基金
High content analgesic screening from human nociceptors
从人类伤害感受器中筛选高含量镇痛剂
- 批准号:1057804210578042
- 财政年份:2023
- 资助金额:$ 56.2万$ 56.2万
- 项目类别:
Role of Primary Sensory Neuron CaMKII Signaling in Regulation of Pain
初级感觉神经元 CaMKII 信号传导在疼痛调节中的作用
- 批准号:1065688610656886
- 财政年份:2023
- 资助金额:$ 56.2万$ 56.2万
- 项目类别:
Targeting visceral pain through intestinal neuropod cell GUCY2C signaling
通过肠道神经足细胞 GUCY2C 信号传导治疗内脏疼痛
- 批准号:1083729310837293
- 财政年份:2023
- 资助金额:$ 56.2万$ 56.2万
- 项目类别:
CaV2.2 splice variants in the hippocampus: function and pharmacology
海马 CaV2.2 剪接变异体:功能和药理学
- 批准号:1036311610363116
- 财政年份:2022
- 资助金额:$ 56.2万$ 56.2万
- 项目类别:
CaV2.2 splice variants in the hippocampus: function and pharmacology
海马 CaV2.2 剪接变异体:功能和药理学
- 批准号:1065227610652276
- 财政年份:2022
- 资助金额:$ 56.2万$ 56.2万
- 项目类别: