Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, 300052, PR China; Tianjin Research Institute of Anesthesiology, Tianjin, 300052, PR China.
Department of Anesthesiology, Tianjin First Central Hospital, Tianjin, 300192, PR China.
Neurosci Lett. 2021 Jun 11;755:135847. doi: 10.1016/j.neulet.2021.135847. Epub 2021 Mar 24.
The development and maintenance of morphine tolerance showed association with neuroinflammation and dysfunction of central glutamatergic system (such as nitration of glutamate transporter). Recent evidence indicated that hydrogen could reduce the levels of neuroinflammation and oxidative stress, but its role in morphine tolerance has not been studied. The rats were intrathecally administered with morphine (10 μg/10 μL each time, twice/day for 5 days). Hydrogen enriched saline (HS) or saline was given intraperitoneally at 1, 3 and 10 mL/kg for 10 min before each dose of morphine administration. The tail-flick latency, mechanical threshold and thermal latency were assessed one day (baseline) before and daily for up to 5 days during morphine injection. The pro-inflammatory cytokine expressions [tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), IL-6)] (by western blotting), astrocyte activation (by immunofluorescence and western blotting), and nitration of glutamate transporter-1 (GLT-1) and glutamine synthetase (GS) (by immunoprecipitation), membrane and total expression of N-methyl-d-aspartic acid (NMDA) receptor NR1 and NR2B subunits were carried out in the spinal dorsal horns. Chronic morphine administration induced antinociceptive tolerance, and together led to increased TNF-α, IL-1β and IL-6 expression, astrocyte activation, GLT-1 and GS nitration, increased membrane and total NR1, NR2B expression. Injection of HS attenuated morphine tolerance in a dose-dependent manner, decreased proinflammatory cytokine expression, inhibited astrocyte activation, decreased GLT-1 and GS nitration, and inhibited membrane trafficking of NMDA receptor. Our result showed that hydrogen pretreatment prevented morphine tolerance by reducing neuroinflammation, GLT-1, GS nitration, NMDA receptor trafficking in the spinal dorsal horn. Pretreatment with hydrogen might be considered as a novel therapeutic strategy for the prevention of morphine tolerance.
吗啡耐受的发展和维持与神经炎症和中枢谷氨酸能系统功能障碍（如谷氨酸转运体硝化）有关。最近的证据表明，氢气可以降低神经炎症和氧化应激的水平，但它在吗啡耐受中的作用尚未得到研究。大鼠鞘内给予吗啡（每次 10μg/10μL，每天两次，共 5 天）。氢盐水（HS）或生理盐水在每次给予吗啡前 10min 腹腔内给予，剂量为 1、3 和 10mL/kg。在吗啡注射前一天（基线）和注射后 5 天内每天评估尾部闪烁潜伏期、机械阈值和热潜伏期。在脊髓背角进行促炎细胞因子表达[肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）、IL-6]（通过western blot）、星形胶质细胞激活（通过免疫荧光和 western blot）、谷氨酸转运体-1（GLT-1）和谷氨酰胺合成酶（GS）硝化（通过免疫沉淀）以及 N-甲基-D-天冬氨酸（NMDA）受体 NR1 和 NR2B 亚基的膜和总表达。慢性吗啡给药诱导抗伤害性耐受，并共同导致 TNF-α、IL-1β 和 IL-6 表达增加、星形胶质细胞激活、GLT-1 和 GS 硝化增加、膜和总 NR1、NR2B 表达增加。HS 注射以剂量依赖性方式减弱吗啡耐受，降低促炎细胞因子表达，抑制星形胶质细胞激活，减少 GLT-1 和 GS 硝化，抑制 NMDA 受体膜转运。我们的结果表明，氢气预处理通过减少脊髓背角的神经炎症、GLT-1、GS 硝化和 NMDA 受体转运，预防吗啡耐受。氢气预处理可能被认为是预防吗啡耐受的一种新的治疗策略。
