Peptidergic intraepidermal nerve fibers in the skin contribute to the neuropathic pain in paclitaxel-induced peripheral neuropathy
Peptidergic intraepidermal nerve fibers in the skin contribute to the neuropathic pain in paclitaxel-induced peripheral neuropathy
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DOI：
10.1016/j.npep.2014.02.001
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发表时间：
2014-06-01
期刊：
影响因子：
2.9
通讯作者：
Tseng, To-Jung
中科院分区：
文献类型：
--
作者：
Ko, Miau-Hwa;Hu, Ming E.;Tseng, To-Jung
在临床策略中，紫杉醇在化疗诱导的周围神经病变（CIPN）中主要对神经性疼痛具有剂量限制作用。在本研究中，紫杉醇CIPN神经病理性疼痛和神经变性之间的关系进行了研究。将成年雄性Sprague-Dawley（SD）大鼠分为三个紫杉醇组（0.5、1.0、2.0 mg/kg）和媒介物组，其中四个腹膜内（i. p.）隔日注射。我们的研究结果表明，紫杉醇组显着表现出减少热痛觉过敏和机械异常性疼痛。紫杉醇的神经毒性表现为后爪无毛皮肤表皮内神经纤维的变性。然而，紫杉醇对肽能IENF的影响甚至未知。紫杉醇组中蛋白基因产物9.5（PGP 9.5）-免疫反应性（IR）IENF的皮肤神经支配显示在整个实验期间密度水平分别降低（73.54 +/-0.72%，63.17 +/-1.77%，61.79 +/-2.68%;相对于载体组，p < 0.05）。此外，紫杉醇组中肽能物质P（SP）-IR IENF的密度水平显著降低（分别为48.84 +/-1.74%，30.02 +/-1.69%，30.14 +/-0.37%;与载体组相比，p < 0.05）。相反，紫杉醇组中肽能降钙素基因相关肽（CGRP）-IR IENF的密度显示出相似的降低水平（分别为82.75 +/-0.91%，84.34 +/-3.20%，81.99 +/-0.25%;与载体组相比，p < 0.05）。线性回归分析显示，PGP9.5、SP、CGRP的IENF密度与戒断痛阈（r（2）= 0.77，p < 0.0001; r（2）= 0.75，p <0.0001; r（2）= 0.28，p = 0.0001）和机械阈值（r（2）= 0.43，p <0.0001）相关。
Paclitaxel in chemotherapy-induced peripheral neuropathy (CIPN) is predominantly with a dose-limiting effect on neuropathic pain in clinical strategy. In the present study, the relationship between the neuropathic pain and nerve degeneration in paclitaxel CIPN was investigated. Adult male Sprague-Dawley (SD) rats were divided into three paclitaxel groups (0.5, 1.0, 2.0 mg/kg) and a vehicle group with four intraperitoneal (i.p.) injections on alternating days. Our results demonstrated that the paclitaxel groups significantly exhibited the reductions of thermal hyperalgesia and mechanical allodynia. The neurotoxicity of paclitaxel conveyed the degeneration of intraepidermal nerve fibers (IENFs) in hindpaw glabrous skin. Nevertheless, the influence of paclitaxel to the peptidergic IENFs are even unknown. The skin innervation of protein gene product 9.5 (PGP 9.5)-immunoreactive (IR) IENFs in paclitaxel groups revealed the decreasing levels of density (73.54 +/- 0.72%, 63.17 +/- 1.77%, 61.79 +/- 2.68%, respectively; vs. vehicle group, p < 0.05) throughout the entire experimental period. Additionally, the diminishing levels of density for peptidergic substance P (SP)-IR IENFs in paclitaxel groups were significantly shown (48.84 +/- 1.74%, 30.02 +/- 1.69%, 30.14 +/- 0.37%, respectively; vs. vehicle group, p < 0.05). On the contrary, the density for peptidergic calcitonin gene-related peptide (CGRP)-IR IENFs in paclitaxel groups were revealed the similar decreasing levels (82.75 +/- 0.91%, 84.34 +/- 3.20%, 81.99 +/- 0.25%, respectively; vs. vehicle group, p < 0.05). Linear regression analyses exhibited that densities of IENFs for PGP 9.5, SP, CGRP were correlated with withdrawal latencies (r(2) = 0.77, p < 0.0001; r(2) = 0.75, p < 0.0001; r2 = 0.28, p = 0.0001, respectively) and mechanical thresholds (r(2) = 0.43, p