Imipramine Ameliorates Pain-related Negative Emotion via Induction of Brain-derived Neurotrophic Factor
Imipramine Ameliorates Pain-related Negative Emotion via Induction of Brain-derived Neurotrophic Factor
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DOI：
10.1007/s10571-014-0097-y
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发表时间：
2014-08
影响因子：
4
通讯作者：
S. Yasuda;Mitsuhiro Yoshida;H. Yamagata;Yasutake Iwanaga;Hiromi Suenaga;K. Ishikawa;M. Nakano;
中科院分区：
文献类型：
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作者：
S. Yasuda;Mitsuhiro Yoshida;H. Yamagata;Yasutake Iwanaga;Hiromi Suenaga;K. Ishikawa;M. Nakano;
抑郁样行为常常因慢性疼痛而变得复杂。包括丙咪嗪 (IMI) 在内的抗抑郁药广泛用于治疗慢性疼痛，但其机制尚不完全清楚。脑源性神经营养因子（BDNF）是一种神经调节剂，通过调节突触传递来减少抑郁。我们的目的是基于 BDNF (trkB) 介导的信号传导和慢性疼痛中的基因表达来表征无镇痛 IMI 的抗抑郁作用。在 Sprague-Dawley (SD) 大鼠中构建慢性缩窄性损伤 (CCI) 模型。从 CCI 后第 10 天开始施用 IMI（5 mg/kg，腹腔注射）。使用缩爪潜伏期（PWL）评估疼痛反应，并根据强迫游泳测试中的不动时间判断抑郁程度。使用抗 BDNF 抗体、K252a 或 5,7-二羟色胺 (5,7-DHT) 来检查丙咪嗪的抗抑郁作用。测量前扣带皮层 (ACC)、头端腹内侧延髓 (RVM) 和脊髓中 pERK1/2（免疫组织化学）、5-HT 和 BDNF（ELISA）以及 BDNF mRNA（RT-PCR）的变化。 CCI 后，大鼠表现出 PWL 降低和不动时间增加。低剂量的 IMI 减少了不动时间，但没有镇痛作用。这种抗抑郁作用可被抗 BDNF 抗体、K252a 和 5,7-DHT 逆转。 IMI 减少了与 pCREB 和 BDNF mRNA 减少相关的 pERK1/2 过度激活，并且这些变化可被 5,7-DHT 逆转。这些结果表明，IMI 可以减少与疼痛相关的负面情绪，但不会影响疼痛，并且这种效果可以通过 5-HT 神经元去神经支配和抗 BDNF 治疗来减弱。 IMI 还能使 ERK/CREB 耦合紊乱正常化，从而诱导 BDNF 的产生。这表明 5-HT 和 BDNF 之间可能存在相互作用。
Depression-like behavior is often complicated by chronic pain. Antidepressants including imipramine (IMI) are widely used to treat chronic pain, but the mechanisms are not fully understood. Brain-derived neurotrophic factor (BDNF) is a neuromodulator that reduces depression by regulating synaptic transmission. We aimed to characterize the antidepressant effects of IMI without analgesia based on BDNF (trkB)-mediated signaling and gene expression in chronic pain. A chronic constriction injury (CCI) model was constructed in Sprague-Dawley (SD) rats. IMI (5 mg/kg, i.p.) was administered from day 10 after CCI. The pain response was assessed using the paw withdrawal latency (PWL) and depression was judged from the immobility time in a forced swim test. Anti-BDNF antibody, K252a, or 5,7-dihydroxytryptamine (5,7-DHT) were used to examine the antidepressant effects of imipramine. Changes in pERK1/2 (immunohistochemistry), 5-HT and BDNF (ELISA), and BDNF mRNA (RT-PCR) were measured in the anterior cingulate cortex (ACC), rostral ventromedial medulla (RVM), and spinal cord. After CCI, rats showed decreased PWL and increased immobility time. A low dose of IMI reduced the immobility time without having analgesic effects. This antidepressant effect was reversed by anti-BDNF antibody, K252a, and 5,7-DHT. IMI reduced excessive activation of pERK1/2 associated with decreased pCREB and BDNF mRNA, and these changes were reversed by 5,7-DHT. These results show that IMI reduces pain-related negative emotion without influencing pain and that this effect is diminished by denervation of 5-HT neurons and by anti-BDNF treatment. IMI also normalizes derangement of ERK/CREB coupling, which leads to induction of BDNF. This suggests a possible interaction between 5-HT and BDNF.