From the Department of Anesthesiology, West China Hospital of Sichuan University, Chengdu, People's Republic of China.
Department of Anesthesiology, The First Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China.
Anesth Analg. 2019 Aug;129(2):587-597. doi: 10.1213/ANE.0000000000003563.
Neuropathic pain is often associated with depression. Enhancing endocannabinoids by fatty acid amide hydrolase (FAAH) inhibitors relieves neuropathic pain and stress-induced depressive-like behaviors in animal models. However, it is unclear whether FAAH inhibitor can relieve neuropathic pain-induced depression by or not by its antinociceptive effects.
Adult male Wistar rats with chronic constriction injury (CCI) to the sciatic nerve were treated with the systemic FAAH inhibitor URB597 (5.8 mg·kg·day, intraperitoneally) or peripherally acting FAAH inhibitor URB937 (1.6 mg·kg·d, intraperitoneally; n = 11-12). The treatment was applied from the 15th day after surgery and continued for 15 days. Mechanical withdrawal threshold was examined by Von Frey test before surgery and on the 28th day after CCI. Depressive-like behaviors were evaluated by forced swimming test (FST) and novelty-suppressed feeding (NSF) after 15-day treatment. The levels of anandamide and 2-arachidonoylglycerol in hippocampus were examined by liquid chromatography and mass spectrometry. Hippocampal neurogenesis including proliferation, differentiation, and survival of newborn cells was assessed by immunohistochemistry.
After CCI injury, the rats developed significantly nociceptive and depressive-like behaviors, indicated by persistent mechanical hypersensitivity in Von Frey test, significantly prolonged immobility time in FST (sham: 84.2 ± 13.4 seconds versus CCI: 137.9 ± 18.8 seconds; P < .001), and protracted latency to feed in NSF (sham: 133.4 ± 19.4 seconds versus CCI: 234.9 ± 33.5 seconds; P < .001). For the CCI rats receiving treatment, compared to vehicle placebo group, pain threshold was increased by both URB597 (3.1 ± 1.0 vs 11.2 ± 1.2 g; P < .001) and URB937 (3.1 ± 1.0 vs 12.1 ± 1.3 g; P < .001). Immobility time of FST was reduced by URB597 (135.8 ± 16.6 vs 85.3 ± 17.2 seconds; P < .001) but not by URB937 (135.8 ± 16.6 vs 129.6 ± 17.8 seconds; P = .78). Latency to feed in NSF was also reduced by URB597 (235.9 ± 30.5 vs 131.8 ± 19.8 seconds; P < .001) but not by URB937 (235.9 ± 30.5 vs 232.2 ± 33.2 seconds; P = .72). Meanwhile, CCI decreased the number of proliferating cells and reduced survival of new mature neurons in hippocampus. URB597 but not URB937 treatment improved these cellular deficits.
Inhibition of FAAH can improve depressive-like behaviors induced by neuropathic pain independent of its peripheral antinociceptive action. Enhanced neurogenesis in hippocampus might contribute to the antidepressive effects of URB597.
神经病理性疼痛常伴有抑郁。通过脂肪酸酰胺水解酶（FAAH）抑制剂增强内源性大麻素可以缓解动物模型中的神经病理性疼痛和应激诱导的抑郁样行为。然而，尚不清楚 FAAH 抑制剂是否通过其镇痛作用来缓解神经病理性疼痛引起的抑郁。
对坐骨神经慢性缩窄性损伤（CCI）的成年雄性 Wistar 大鼠用全身性 FAAH 抑制剂 URB597（5.8 mg·kg·天，腹腔内注射）或外周作用 FAAH 抑制剂 URB937（1.6 mg·kg·d，腹腔内注射；n = 11-12）进行治疗。治疗从手术后第 15 天开始，持续 15 天。在手术前和 CCI 后第 28 天通过 Von Frey 试验检查机械撤回避触阈值。在 15 天治疗后通过强迫游泳试验（FST）和新奇抑制进食试验（NSF）评估抑郁样行为。通过液相色谱和质谱法检测海马体中的花生四烯酸和 2-花生四烯酰甘油水平。通过免疫组织化学评估新生细胞的增殖、分化和存活情况。
CCI 损伤后，大鼠出现明显的痛觉和抑郁样行为，Von Frey 试验中持续的机械超敏反应、FST 中明显延长的不动时间（假手术：84.2 ± 13.4 秒与 CCI：137.9 ± 18.8 秒；P <.001）和 NSF 中潜伏期延长进食（假手术：133.4 ± 19.4 秒与 CCI：234.9 ± 33.5 秒；P <.001）表明。与vehicle 安慰剂组相比，CCI 大鼠接受治疗后，URB597（3.1 ± 1.0 对 11.2 ± 1.2 g；P <.001）和 URB937（3.1 ± 1.0 对 12.1 ± 1.3 g；P <.001）的痛觉阈值增加。URB597 降低 FST 的不动时间（135.8 ± 16.6 对 85.3 ± 17.2 秒；P <.001），但 URB937 不降低（135.8 ± 16.6 对 129.6 ± 17.8 秒；P =.78）。URB597 还降低 NSF 的潜伏期进食（235.9 ± 30.5 对 131.8 ± 19.8 秒；P <.001），但 URB937 不降低（235.9 ± 30.5 对 232.2 ± 33.2 秒；P =.72）。同时，CCI 减少了海马体中增殖细胞的数量，并降低了新成熟神经元的存活。URB597 治疗而非 URB937 治疗改善了这些细胞缺陷。
FAAH 的抑制可以改善神经病理性疼痛引起的抑郁样行为，而不依赖于其外周镇痛作用。增强海马体中的神经发生可能有助于 URB597 的抗抑郁作用。
