Sex-specific role of the circadian transcription factor NPAS2 in opioid tolerance, withdrawal and analgesia.
Sex-specific role of the circadian transcription factor NPAS2 in opioid tolerance, withdrawal and analgesia.
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DOI：
10.1111/gbb.12829
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发表时间：
2022-09
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影响因子：
--
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芬太尼等阿片类药物仍然是治疗慢性疼痛的主要药物。不幸的是，阿片类药物的高依赖性导致了目前的阿片类药物危机，部分原因是长期使用过程中产生的副作用，包括镇痛耐受性和身体依赖性。对阿片类药物的耐受性和依赖性都可能导致所需剂量的增加，以达到先前的治疗效果。此外，睡眠和昼夜节律的改变在阿片类药物治疗的人群中很常见。阿片类药物影响睡眠和昼夜节律，而睡眠和昼夜节律的中断可能介导阿片类药物的作用。然而，昼夜节律和阿片类药物之间的双向关系的机制在很大程度上仍然未知。昼夜节律蛋白，神经元PAS结构域蛋白2（NPAS 2），调节中枢神经系统结构中的昼夜节律依赖性基因转录，调节阿片类药物和疼痛。在这里，雄性和雌性野生型和NPAS 2缺陷（NPAS 2-/-）小鼠被用来研究NPAS 2在芬太尼镇痛，耐受，痛觉过敏和身体依赖中的作用。总的来说，热痛阈值，急性镇痛和对固定剂量芬太尼的耐受性在野生型和NPAS 2 −/−小鼠之间基本相似。然而，女性NPAS 2 −/−表现出增强的镇痛耐受性和对芬太尼的身体依赖的行为症状。与野生型雄性相比，只有雄性NPAS 2 −/−小鼠的芬太尼诱导超敏反应增加。总之，我们的研究结果表明NPAS 2信号在芬太尼诱导的耐受性，痛觉过敏和依赖性的调节中具有性别特异性作用。昼夜节律转录因子NPAS 2的缺乏导致雌性小鼠对芬太尼的身体依赖性增强。
Opioids like fentanyl remain the mainstay treatment for chronic pain. Unfortunately, opioid's high dependence liability has led to the current opioid crisis, in part, because of side‐effects that develop during long‐term use, including analgesic tolerance and physical dependence. Both tolerance and dependence to opioids may lead to escalation of required doses to achieve previous therapeutic efficacy. Additionally, altered sleep and circadian rhythms are common in people on opioid therapy. Opioids impact sleep and circadian rhythms, while disruptions to sleep and circadian rhythms likely mediate the effects of opioids. However, the mechanisms underlying these bidirectional relationships between circadian rhythms and opioids remain largely unknown. The circadian protein, neuronal PAS domain protein 2 (NPAS2), regulates circadian‐dependent gene transcription in structure of the central nervous system that modulate opioids and pain. Here, male and female wild‐type and NPAS2‐deficient (NPAS2−/−) mice were used to investigate the role of NPAS2 in fentanyl analgesia, tolerance, hyperalgesia and physical dependence. Overall, thermal pain thresholds, acute analgesia and tolerance to a fixed dose of fentanyl were largely similar between wild‐type and NPAS2−/− mice. However, female NPAS2−/− exhibited augmented analgesic tolerance and significantly more behavioral symptoms of physical dependence to fentanyl. Only male NPAS2−/− mice had increased fentanyl‐induced hypersensitivity, when compared with wild‐type males. Together, our findings suggest sex‐specific effects of NPAS2 signaling in the regulation of fentanyl‐induced tolerance, hyperalgesia and dependence. Deficiency of the circadian transcription factor NPAS2 leads to augmented physical dependence to fentanyl in female mice.
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DOI：
10.1111/j.1440-1681.1995.tb02012.x
发表时间：
1995-05-01
影响因子：
2.9
作者：
ALI, BH;SHARIF, SI;ELKADI, A
通讯作者：
ELKADI, A
影响因子：
5.3
作者：
DePoy, Lauren M.;Becker-Krail, Darius D.;McClung, Colleen A.
通讯作者：
McClung, Colleen A.
影响因子：
3.5
作者：
Chun, Lauren E.;Woodruff, Elizabeth R.;Spencer, Robert L.
通讯作者：
Spencer, Robert L.
影响因子：
8.2
作者：
Bumgarner JR;Walker WH 2nd;Nelson RJ
通讯作者：
Nelson RJ
影响因子：
5.7
作者：
Cepeda, MS;Carr, DB
通讯作者：
Carr, DB