Department of Endocrinology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, People's Republic of China.
Laboratories of Clinical and Experimental Pathology.
Pain Med. 2018 Mar 1;19(3):580-588. doi: 10.1093/pm/pnx125.
Although duloxetine has been approved for clinical therapy for diabetic peripheral neuropathic pain, the exact mechanism underlying the anti-allodynic effects in rat models of diabetes mellitus remains obscure. We attempted to identify whether duloxetine exerts anti-allodynic effects via inhibition of the TLR4-Myd88-dependent pathway in diabetic neuropathic pain (DNP) rats.
An animal model of type 1 diabetic neuropathic pain was induced by intraperitoneal streptozotocin in 108 rats randomized into four groups: control, DNP, solvent control + DNP, and DNP + duloxetine. The DNP model establishment was validated, providing the MWT and TWL measurements were less than 80% of the baseline value on d14 after streptozotocin administration. The expressions of TLR4, Myd88, and NF-κB in the spinal dorsal horn were determined 21 days after streptozotocin injection by immunohistochemical assay and Western blot.
The results revealed that MWT and TWL in DNP, SC + DNP, and DLX + DNP groups were significantly decreased 14 days after STZ administration vs control (P < 0.05), while the pain thresholds in the DLX + DNP group were partially reversed. The expressions of TLR4, Myd88, and NF-κB in groups C, DNP, and SC + DNP were significantly increased, whereas duloxetine administration significantly downregulated the expressions of TLR4, Myd88, and NF-κB (P < 0.05).
Our findings indicated that duloxetine mitigated mechanical and thermal withdrawal thresholds in STZ-injected rats and rescued the overexpression of the TLR4-Myd88-dependent pathway in the spinal dorsal horn in these rats. Whether these changes directly contributed to the reduction of thermal and mechanical withdrawal behavior needs to be further explored.
尽管度洛西汀已被批准用于治疗糖尿病周围神经性疼痛的临床治疗，但在糖尿病模型大鼠中其抗痛觉过敏的确切机制仍不清楚。我们试图确定度洛西汀是否通过抑制 TLR4-Myd88 依赖性通路在糖尿病神经病理性疼痛（DNP）大鼠中发挥抗痛觉过敏作用。
108 只大鼠随机分为 4 组：对照组、DNP 组、溶剂对照组+DNP 组和 DNP+度洛西汀组，通过腹腔内链脲佐菌素诱导 1 型糖尿病神经病理性疼痛动物模型。DNP 模型建立后，通过测量机械缩足阈值（MWT）和热缩足潜伏期（TWL），当 MWT 和 TWL 小于链脲佐菌素给药后第 14 天基线值的 80%时，表明模型建立成功。免疫组化和 Western blot 检测 TLR4、Myd88 和 NF-κB 在脊髓背角的表达。
结果显示，与对照组相比，DNP 组、SC+DNP 组和 DLX+DNP 组在 STZ 给药后 14 天 MWT 和 TWL 明显降低（P<0.05），而 DLX+DNP 组的痛觉阈值部分恢复。与 C 组、DNP 组和 SC+DNP 组相比，TLR4、Myd88 和 NF-κB 的表达在各组均显著增加，而度洛西汀治疗则显著下调了 TLR4、Myd88 和 NF-κB 的表达（P<0.05）。
我们的研究结果表明，度洛西汀可减轻 STZ 注射大鼠的机械和热缩足阈值，并挽救这些大鼠脊髓背角 TLR4-Myd88 依赖性通路的过度表达。这些变化是否直接导致热和机械退缩行为的减少还需要进一步探讨。
