Resolvin D1 reverses chronic pancreatitis-induced mechanical allodynia, phosphorylation of NMDA receptors, and cytokines expression in the thoracic spinal dorsal horn.
Resolvin D1 reverses chronic pancreatitis-induced mechanical allodynia, phosphorylation of NMDA receptors, and cytokines expression in the thoracic spinal dorsal horn.
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Resolvin D1 可逆转慢性胰腺炎引起的机械性异常性疼痛、NMDA 受体磷酸化以及胸椎背角细胞因子的表达
DOI：
10.1186/1471-230x-12-148
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发表时间：
2012-10-23
影响因子：
2.4
通讯作者：
Wei W
中科院分区：
文献类型：
--
作者：
Quan-Xin F;Fan F;Xiang-Ying F;Shu-Jun L;Shi-Qi W;Zhao-Xu L;Xu-Jie Z;Qing-Chuan Z;Wei W
背景我们先前报道，脊髓背角的免疫激活参与了慢性胰腺炎(CP)引起的疼痛。中枢神经系统的靶向免疫反应可能为CP引起的疼痛提供有效的治疗方法。最近的研究表明，解决素D 1(RvD 1)可以有效地抑制炎性疼痛。我们推测鞘内注射RvD_1可抑制慢性前列腺炎大鼠的疼痛。所有大鼠被分成三组：TNBS组、假手术组和单纯对照组，并进一步分为鞘内注射RvD1组。用von Frey纤维测试大鼠的疼痛行为。采用旷场实验和高架+迷宫实验评价大鼠的焦虑样行为和自由活动探索能力。苏木精-伊红染色观察胰腺组织学改变。用Western印迹、实时定量RT-PCR和ELISA检测NMDA受体的磷酸化和炎性细胞因子的表达。结果行为学研究表明，与空白对照组相比，RvD1(100 ng/kg)在给药后2 h显著降低TNBS诱导的机械痛敏反应(反应频率：49.2±3.7%vs71.3±6.1%)，且这种作用呈剂量依赖关系。CP和RvD1治疗均不能影响焦虑样行为。CP或RvD1处理不影响大鼠的自由活动和探索能力。Western印迹分析显示，与单纯组相比，TNBS组大鼠脊髓中磷酸化NR1(PNR1)和pNR2B的表达显著增加(分别为单纯组的3.87±0.31倍和单纯组的4.17±0.24倍)。与空白对照组相比，10 ng/kg的RvD1可显著抑制pNR1和pNR2B的表达(分别为2.21±0.26倍和3.31±0.34倍)。实时荧光定量RT-PCR和酶联免疫吸附试验结果显示，RvD_1(10 ng/kg)组可显著抑制肿瘤坏死因子-α、IL-1β和IL-6的表达，而赋形剂无明显作用。此外，RvD1不影响假手术大鼠的疼痛行为、NMDA受体磷酸化或细胞因子的产生。结论RvD1有望成为治疗CP慢性疼痛的一种新的有效方法。
BackgroundWe previously reported that immune activation in the spinal dorsal horn contributes to pain induced by chronic pancreatitis (CP). Targeting immune response in the CNS may provide effective treatments for CP-induced pain. Recent findings demonstrate that resolvin D1 (RvD1) can potently dampen inflammatory pain. We hypothesized that intrathecal injection of RvD1 may inhibit pain of CP.MethodsRat CP model was built through intrapancreatic infusion of trinitrobenzene sulfonic acid (TNBS). All the rats were divided into three groups: TNBS, sham, and naïve controls and were further divided for intrathecal RvD1 administration. Pain behavior of rats was tested with von Frey filaments. Anxiety-like behavior and free locomotor and exploration of rats were evaluated by open field test and elevated plus maze. Pancreatic histology was evaluated with hematoxylin and eosin staining. Phosphorylation of NMDA receptor and expression of inflammatory cytokines were examined with Western blot, real-time RT-PCR and ELISA.ResultsBehavioral study indicated that compared to the vehicle control, RvD1 (100 ng/kg) significantly decreased TNBS-induced mechanical allodynia at 2 h after administration (response frequencies: 49.2 ± 3.7%vs71.3 ± 6.1%), and this effect was dose-dependent. Neither CP nor RvD1 treatment could affect anxiety-like behavior. CP or RvD1 treatment could not affect free locomotor and exploration of rats. Western blot analysis showed that compared with that of naïve group, phosphorylated NR1 (pNR1) and pNR2B in TNBS rats were significantly increased in the spinal cord (pNR1: 3.87±0.31 folds of naïve control, pNR2B: 4.17 ± 0.24 folds of naïve control). Compared to vehicle control, 10 ng/kg of RvD1 could significantly block expressions of pNR1 (2.21 ± 0.26 folds of naïve) and pNR2B (3.31 ± 0.34 folds of naïve). Real-time RT-PCR and ELISA data showed that RvD1 (10 ng/kg) but not vehicle could significantly block expressions of TNF-alpha, IL-1beta and IL-6. In addition, RvD1 did not influence pain behavior, NMDA receptor phosphorylation or cytokines production in sham-operated rats.ConclusionsThese data highly suggest that RvD1 could be a novel and effective treatment for CP-induced chronic pain.