Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL 33136, United States.
Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL 33136, United States.
Exp Neurol. 2021 May;339:113622. doi: 10.1016/j.expneurol.2021.113622. Epub 2021 Jan 29.
Opioid use disorders (OUDs) have reached an epidemic level in the United States. The opioid epidemic involves illicit opioid use, prescription opioids for analgesia, counterfeit opioids, new psychoactive substances, and diverted opioids. Opioids remain the last option for the treatment of intractable clinical pain, but chronic use of opioids are limited in part due to antinociceptive/analgesic tolerance. Peroxisome proliferator-activated receptor (PPAR)-gamma coactivator-1alpha (PGC-1α), a mitochondrial biogenesis factor can reduce toxic reactive oxygen species (ROS) that play a role in morphine tolerance (MT). Decreased PGC-1α expression has been shown to contribute to various metabolic disorders or neurodegeneration diseases through increasing ROS. We examined the relationship of PGC-1α and ROS in MT. To induce MT, adult Sprague-Dawley rats received intrathecal morphine for 7 days. Mechanical threshold was measured using the von Frey test and thermal latency was examined using the heat plate test. Expression of PGC-1α in the spinal cord dorsal horn (SCDH) was examined using RT-PCR and western blots. Mitochondrial superoxide was detected using MitoSox Red, a mitochondrial superoxide indicator. The antinociceptive effect of recombinant PGC-1α (rPGC-1α) or Mito-Tempol (a mitochondria-targeted superoxide scavenger) was determined using the von Frey test and hot plate test. Furthermore, we examined the effect of rPGC-1α on mitochondrial superoxide using cultured neurons. Our findings include that: (i) spinal MT decreased the expression of spinal PGC-1α in the SCDH neurons; (ii) rPGC-1α increased mechanical threshold and thermal latency in MT animals; (iii) Mito-Tempol reduced MT behavioral response; (iv) rPGC-1α reduced MT-induced mitochondria-targeted superoxide; and (v) cultured neuronal cells treated with TNFα increased mitochondria-targeted superoxide that can be inhibited by rPGC-1α. The present findings suggest that spinal PGC-1α reduce MT through decreasing mitochondria-targeted superoxide in the SCDH.
阿片类药物使用障碍（OUDs）在美国已达到流行水平。阿片类药物流行涉及非法阿片类药物使用、用于镇痛的处方阿片类药物、假冒阿片类药物、新精神活性物质和转移阿片类药物。阿片类药物仍然是治疗顽固性临床疼痛的最后选择，但由于阿片类药物的抗伤害感受/镇痛耐受，慢性使用受到限制。过氧化物酶体增殖物激活受体（PPAR）-γ共激活因子 1α（PGC-1α）是一种线粒体生物发生因子，可以减少在吗啡耐受（MT）中起作用的有毒活性氧物种（ROS）。已经表明，PGC-1α表达的减少通过增加 ROS 导致各种代谢紊乱或神经退行性疾病。我们检查了 PGC-1α与 MT 中 ROS 的关系。为了诱导 MT，成年 Sprague-Dawley 大鼠接受鞘内吗啡治疗 7 天。使用 von Frey 测试测量机械阈值，使用热板测试检查热潜伏期。使用 RT-PCR 和 Western blot 检查脊髓背角（SCDH）中 PGC-1α的表达。使用 MitoSox Red（一种线粒体超氧化物指示剂）检测线粒体超氧化物。使用 von Frey 测试和热板测试确定重组 PGC-1α（rPGC-1α）或 Mito-Tempol（一种线粒体靶向超氧化物清除剂）的镇痛作用。此外，我们还研究了 rPGC-1α对培养神经元中线粒体超氧化物的影响。我们的发现包括：（i）脊髓 MT 降低了 SCDH 神经元中脊髓 PGC-1α的表达；（ii）rPGC-1α增加了 MT 动物的机械阈值和热潜伏期；（iii）Mito-Tempol 降低了 MT 行为反应；（iv）rPGC-1α减少了 MT 诱导的线粒体靶向超氧化物；和（v）用 TNFα 处理的培养神经元细胞增加了线粒体靶向超氧化物，可被 rPGC-1α 抑制。本研究结果表明，脊髓 PGC-1α 通过减少 SCDH 中线粒体靶向超氧化物来减少 MT。
