Behavioral Neuroscience Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health, DHHS, Baltimore, MD, USA.
Neuropsychopharmacology. 2018 Mar;43(4):810-819. doi: 10.1038/npp.2017.181. Epub 2017 Aug 29.
Fentanyl is a potent synthetic opioid used extensively in humans for general anesthesia and analgesia. Fentanyl has emerged as a recreational drug, often in combination with heroin, and can result in lethality during overdose. Fentanyl is well characterized as an anesthetic, but the basic physiological effects of fentanyl in the brain when taken as a drug of abuse are largely unknown. We used high-speed amperometry in freely moving rats to examine the effects of intravenous fentanyl at doses within the range of possible human intake (3-40 μg/kg) on oxygen and glucose levels in nucleus accumbens (NAc). Fentanyl induced a rapid, dose-dependent decrease in NAc oxygen followed by a more delayed and prolonged increase in NAc glucose. Fentanyl induced similar oxygen decreases in the basolateral amygdala, indicating that brain hypoxia could be a generalized phenomenon. We used oxygen recordings in the subcutaneous space to confirm that fentanyl-induced brain hypoxia results from decreases in blood oxygen levels caused by drug-induced respiratory depression. Temperature recordings in the NAc, muscle, and skin showed that fentanyl induces biphasic changes in brain temperature, with an initial decrease that results primarily from peripheral vasodilation, and a subsequent increase driven by metabolic brain activation. The initial vasodilation appears caused by respiratory depression-induced hypoxia and a subsequent rise in CO that drives fentanyl-induced increases in NAc glucose. Together, these data suggest that fentanyl-induced respiratory depression triggers brain hypoxia and subsequent hyperglycemia, both of which precede slower changes in brain temperature and metabolic brain activity.
芬太尼是一种强效的合成阿片类药物，广泛用于人类全身麻醉和镇痛。芬太尼已成为一种娱乐性药物，通常与海洛因混合使用，过量使用会导致致命。芬太尼作为一种麻醉剂的特性已经得到很好的描述，但作为滥用药物时，其在大脑中的基本生理效应在很大程度上尚不清楚。我们使用高速安培法在自由活动的大鼠中研究了静脉内芬太尼在可能的人类摄入范围内（3-40μg/kg）对伏隔核（NAc）中氧和葡萄糖水平的影响。芬太尼诱导了 NAc 氧的快速、剂量依赖性降低，随后是更延迟和延长的 NAc 葡萄糖增加。芬太尼在基底外侧杏仁核中引起类似的氧降低，表明脑缺氧可能是一种普遍现象。我们使用皮下空间中的氧记录来证实，芬太尼诱导的脑缺氧是由于药物引起的呼吸抑制导致的血氧水平降低引起的。NAc、肌肉和皮肤中的温度记录表明，芬太尼诱导脑温度的双相变化，最初的降低主要是由于外周血管扩张，随后的增加是由代谢性脑激活驱动的。最初的血管扩张似乎是由呼吸抑制引起的缺氧和随后的 CO 升高引起的，这两者都导致芬太尼诱导的 NAc 葡萄糖增加。总之，这些数据表明，芬太尼诱导的呼吸抑制引发脑缺氧和随后的高血糖，这两者都先于较慢的脑温度和代谢性脑活动变化。
