镁和吗啡治疗慢性神经性疼痛的生物医学作用机制。
Magnesium and Morphine in the Treatment of Chronic Neuropathic Pain-A Biomedical Mechanism of Action.
机构信息
Centre for Preclinical Research and Technology, Department of Pharmacodynamics, Medical University of Warsaw, Banacha 1b Str., 02-097 Warsaw, Poland.
Chair and Department of Biochemistry, Medical University of Warsaw, Banacha 1 Str., 02-097 Warsaw, Poland.
出版信息
Int J Mol Sci. 2021 Dec 18;22(24):13599. doi: 10.3390/ijms222413599.
The effectiveness of opioids in the treatment of neuropathic pain is limited. It was demonstrated that magnesium ions (Mg), physiological antagonists of N-methyl-D-aspartate receptor (NMDAR), increase opioid analgesia in chronic pain. Our study aimed to determine the molecular mechanism of this action. Early data indicate the cross-regulation of µ opioid receptor (MOR) and NMDAR in pain control. Morphine acting on MOR stimulates protein kinase C (PKC), while induction of NMDAR recruits protein kinase A (PKA), leading to a disruption of the MOR-NMDAR complex and promoting functional changes in receptors. The mechanical Randall-Selitto test was used to assess the effect of chronic Mg and morphine cotreatment on streptozotocin-induced hyperalgesia in Wistar rats. The level of phosphorylated NMDAR NR1 subunit (pNR1) and phosphorylated MOR (pMOR) in the periaqueductal gray matter was determined with the Western blot method. The activity of PKA and PKC was examined by standard enzyme immunoassays. The experiments showed a reduction in hyperalgesia after coadministration of morphine (5 mg/kg intraperitoneally) and Mg (40 mg/kg intraperitoneally). Mg administered alone significantly decreased the level of pNR1, pMOR, and activity of both tested kinases. The results suggest that blocking NMDAR signaling by Mg restores the MOR-NMDAR complex and thus enables morphine analgesia in neuropathic rats.
阿片类药物治疗神经性疼痛的效果有限。研究表明，镁离子（Mg）作为 N-甲基-D-天冬氨酸受体（NMDAR）的生理性拮抗剂，可增强慢性疼痛中的阿片类药物镇痛作用。本研究旨在确定这种作用的分子机制。早期数据表明，μ 阿片受体（MOR）和 NMDAR 在疼痛控制中存在交叉调节。吗啡作用于 MOR 可刺激蛋白激酶 C（PKC），而 NMDAR 的诱导则招募蛋白激酶 A（PKA），导致 MOR-NMDAR 复合物的破坏，并促进受体的功能变化。机械 Randall-Selitto 测试用于评估慢性 Mg 和吗啡共同处理对链脲佐菌素诱导的 Wistar 大鼠痛觉过敏的影响。Western blot 法测定缰核中磷酸化 NMDAR NR1 亚基（pNR1）和磷酸化 MOR（pMOR）的水平。通过标准酶免疫测定法检查 PKA 和 PKC 的活性。实验表明，吗啡（5mg/kg 腹腔内注射）和 Mg（40mg/kg 腹腔内注射）共同给药后，痛觉过敏减轻。单独给予 Mg 可显著降低 pNR1、pMOR 和两种检测激酶的活性。结果表明，Mg 通过阻断 NMDAR 信号恢复 MOR-NMDAR 复合物，从而使神经性疼痛大鼠能够发挥吗啡镇痛作用。
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