Inhibition of Fatty Acid Amide Hydrolase Improves Depressive-Like Behaviors Independent of Its Peripheral Antinociceptive Effects in a Rat Model of Neuropathic Pain
Inhibition of Fatty Acid Amide Hydrolase Improves Depressive-Like Behaviors Independent of Its Peripheral Antinociceptive Effects in a Rat Model of Neuropathic Pain
复制标题
抑制脂肪酸酰胺水解酶可改善神经性疼痛大鼠模型中的抑郁样行为，与其外周镇痛作用无关
DOI：
10.1213/ane.0000000000003563
复制
发表时间：
2019-08-01
影响因子：
5.7
通讯作者：
Zhou, Cheng
中科院分区：
文献类型：
--
作者：
Jiang, Hai-xia;Ke, Bo-wen;Zhou, Cheng
背景
神经性疼痛通常与抑郁症有关。脂肪酸酰胺水解酶（FAAH）抑制剂增强内源性大麻素缓解动物模型中的神经性疼痛和应激诱导的抑郁样行为。然而，FAAH抑制剂是否通过其抗伤害性作用来减轻神经病理性疼痛引起的抑郁，目前尚不清楚。
方法
用FAAH抑制剂URB 597（5.8mg·kg·d）或外周作用的FAAH抑制剂URB 937（1.6mg·kg·d）治疗慢性坐骨神经压迫性损伤（CCI）的成年雄性Wistar大鼠（n = 11-12）。治疗从术后第15天开始，持续15天。分别于术前和术后第28天用Von Frey试验检测机械性缩足阈。给药15 d后，采用强迫游泳试验（FST）和新奇性抑制摄食（NSF）评价抑郁样行为。采用液相色谱-质谱联用技术检测海马中花生四烯酸和花生四烯酸甘油的含量。海马神经发生包括新生细胞的增殖、分化和存活通过免疫组织化学进行评估。
结果
CCI损伤后，大鼠出现明显的伤害性和抑郁样行为，在Von Frey试验中表现为持续的机械超敏反应，在FST中表现为不动时间明显延长（假手术组：84.2 ± 13.4秒，CCI组：137.9 ± 18.8秒; P <0.001），NSF组进食潜伏期延长（假手术：133.4 ± 19.4秒，CCI：234.9 ± 33.5秒; P <0.001）。对于接受治疗的CCI大鼠，与载体安慰剂组相比，URB 597（3.1 ± 1.0 vs 11.2 ± 1.2 g; P <0.001）和URB 937（3.1 ± 1.0 vs 12.1 ± 1.3 g; P <0.001）均增加了疼痛阈值。URB 597缩短了FST的不动时间（135.8 ± 16.6 vs 85.3 ± 17.2秒; P <0.001），但URB 937没有缩短（135.8 ± 16.6 vs 129.6 ± 17.8秒; P = 0.78）。在NSF中，URB 597也降低了进食潜伏期（235.9 ± 30.5 vs 131.8 ± 19.8秒; P <0.001），但URB 937没有降低（235.9 ± 30.5 vs 232.2 ± 33.2秒; P = 0.72）。同时，CCI减少了海马内增殖细胞的数量，减少了新生成熟神经元的存活。URB 597而不是URB 937治疗改善了这些细胞缺陷。
结论
抑制FAAH可以改善神经病理性疼痛诱导的抑郁样行为，而不依赖于其外周抗伤害作用。海马神经再生的增强可能与URB 597的抗抑郁作用有关。
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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.