Brazile Chet, Fan Ruping, Benoit Beau, Arnold Thomas, Korneeva Nadejda
School of Medicine, LSU Health Shreveport, Shreveport, LA 71103, USA.
Department of Emergency Medicine, LSU Health Shreveport, Shreveport, LA 71103, USA.
Pathophysiology. 2024 Mar 6;31(1):152-165. doi: 10.3390/pathophysiology31010012.
Opioid abuse in the United States has been increasing at an alarming rate over the past 20 years. Sex differences are documented for the rates of opioid-related overdoses, abuse patterns, and drug-induced physiological effects. In our previous study, we demonstrated that chronic oxycodone administration in young female rats is associated with neurodegeneration in the brain. Males and females are susceptible to neurodegenerative diseases via differing mechanisms. To investigate whether opioid exposure affects males and females differently, we treated young mice with chronic morphine. We observed that females had stronger antinociceptive responses to acute morphine and showed a delayed development of tolerance. Males had a higher basal Bax level in the brain that correlated with a higher number of apoptotic cells. Morphine increased Bax levels in both males and females without affecting the numbers of apoptotic cells. Morphine increased activated caspase 3 in axons and increased the MBP level in plasma only in females, suggesting a demyelination process. Our data suggest that males are protected from demyelination by having a higher basal BDNF level. Altogether, our results suggest that males and females have different molecular signaling underlying their patterns in the development of morphine tolerance and drug-induced neuronal degeneration.
在过去20年里，美国阿片类药物滥用现象一直以惊人的速度增长。阿片类药物相关过量用药率、滥用模式及药物诱发的生理效应存在性别差异。在我们之前的研究中，我们证明了在年轻雌性大鼠中长期给予羟考酮与大脑神经退行性变有关。雄性和雌性通过不同机制易患神经退行性疾病。为了研究阿片类药物暴露对雄性和雌性的影响是否不同，我们用慢性吗啡处理年轻小鼠。我们观察到，雌性对急性吗啡的镇痛反应更强，且耐受性发展延迟。雄性大脑中的基础Bax水平较高，这与凋亡细胞数量较多相关。吗啡增加了雄性和雌性的Bax水平，但不影响凋亡细胞数量。吗啡仅在雌性中增加了轴突中活化的半胱天冬酶3水平，并增加了血浆中的髓鞘碱性蛋白水平，提示存在脱髓鞘过程。我们的数据表明，雄性由于基础脑源性神经营养因子水平较高而免受脱髓鞘影响。总之，我们的结果表明，雄性和雌性在吗啡耐受性发展和药物诱发的神经元变性模式中存在不同的分子信号。
