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The effects of chronic high-dose morphine on microgliosis and the microglial transcriptome in rat spinal cord

小胶质细胞 吗啡 医学 伤害 转录组 类阿片 慢性疼痛 脊髓 止痛药 药理学 昼夜节律 炎症 内科学 内分泌学 麻醉 生物 基因表达 受体 基因 生物化学 精神科
作者
Fredrik Ahlström,Hanna Viisanen,Leena Karhinen,Kert Mätlik,Kim Juhani Blomqvist,Tuomas O. Lilius,Yulia Sidorova,Vinko Palada,Pekka Rauhala,Eija Kalso
出处
期刊:Molecular Pain [SAGE Publishing]
卷期号:19 被引量:3
标识
DOI:10.1177/17448069231183902
摘要

Background: Opioids are efficacious and safe analgesic drugs in short-term use for acute pain but chronic use can lead to tolerance and dependence. Opioid-induced microglial activation may contribute to the development of tolerance and this process may differ between males and females. A link is suggested between this microglial activation and inflammation, disturbances of circadian rhythms, and neurotoxic effects. We set out to further delineate the effects of chronic morphine on pain behaviour, microglial and neuronal staining, and the transcriptome of spinal microglia, to better understand the role of microglia in the consequences of long-term high-dose opioid administration. Experimental Approach: In two experiments, we administered increasing subcutaneous doses of morphine hydrochloride or saline to male and female rats. Thermal nociception was assessed with the tail flick and hot plate tests. In Experiment I, spinal cord (SC) samples were prepared for immunohistochemical staining for microglial and neuronal markers. In Experiment II, the transcriptome of microglia from the lumbar SC was analysed. Key Results: Female and male rats had similar antinociceptive responses to morphine and developed similar antinociceptive tolerance to thermal stimuli following chronic increasing high doses of s.c. morphine. The area of microglial IBA1-staining in SC decreased after 2 weeks of morphine administration in both sexes. Following morphine treatment, the differentially expressed genes identified in the microglial transcriptome included ones related to the circadian rhythm , apoptosis, and immune system processes. Conclusions: Female and male rats showed similar pain behaviour following chronic high doses of morphine. This was associated with decreased staining of spinal microglia, suggesting either decreased activation or apoptosis. High-dose morphine administration also associated with several changes in gene expression in SC microglia, e.g., those related to the circadian rhythm ( Per2, Per3, Dbp). These changes should be considered in the clinical consequences of long-term high-dose administration of opioids.
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