Intrathecal Injection of JWH-015 Attenuates Bone Cancer Pain Via Time-Dependent Modification of Pro-inflammatory Cytokines Expression and Astrocytes Activity in Spinal Cord
Intrathecal Injection of JWH-015 Attenuates Bone Cancer Pain Via Time-Dependent Modification of Pro-inflammatory Cytokines Expression and Astrocytes Activity in Spinal Cord
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鞘内注射 JWH-015 通过时间依赖性改变脊髓中促炎细胞因子表达和星形胶质细胞活性来减轻骨癌疼痛
DOI：
10.1007/s10753-015-0168-3
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发表时间：
2015-10-01
期刊：
影响因子：
5.1
通讯作者：
Gu, Xiaoping
中科院分区：
文献类型：
--
作者：
Lu, Cui'e;Liu, Yue;Gu, Xiaoping
大麻素受体2型（CB 2）激动剂在急性和神经性疼痛中显示出潜在的镇痛作用。然而，其在骨癌疼痛中复杂的细胞和分子机制仍不清楚。而关于其对骨癌痛引起的行为学改变、脊髓炎性细胞因子水平、星形胶质细胞活性的时间依赖性影响的相关报道较少。采用胫骨内接种步行者256乳腺癌细胞诱导骨癌疼痛的大鼠模型。采用动态疼痛评分和机械缩爪阈值（PWMT）评价不同时间点的疼痛行为。通过蛋白质印迹法定量促炎细胞因子，如白细胞介素（IL）-1β、IL-6、IL-18和肿瘤坏死因子α（TNF-α）。通过免疫组织化学评估胶质细胞活性。胫骨内接种步行者256乳腺癌细胞诱导进行性骨癌疼痛; IL-1β、IL-6、IL-18和TNF-α的长期上调;以及脊髓中胶质细胞的激活。小胶质细胞的活化在手术后第4天首次明显，并在第7天达到峰值，而星形胶质细胞的活化在第10天。单次鞘内注射JWH-015减轻了骨癌诱导的自发性疼痛和机械性异常性疼痛，减少了促炎细胞因子的表达，并抑制了星形胶质细胞的活性。所有的改变都是短暂的，在JWH-015给药后24 h达到峰值。此外，在CB 2选择性拮抗剂AM 630存在下，JWH-015的保护作用被逆转。总之，我们的研究结果为炎症反应持续参与骨癌疼痛的进展提供了证据，并证明JWH-015以时间依赖的方式降低IL-1β、IL-6、IL-18和TNF-α的表达，抑制星形胶质细胞的活化，从而显示镇痛作用。
Cannabinoid receptor type 2 (CB2) agonists display potential analgesic effects in acute and neuropathic pain. However, its complex cellular and molecular mechanisms in bone cancer pain remain unclear. And less relevant reports concerned its time-dependent effects on the long-lasting modifications of behavior, spinal inflammatory cytokines levels, astrocytes activity induced by bone cancer pain. A rat model of bone cancer pain induced by intra-tibia inoculation of Walker 256 mammary gland carcinoma cells was utilized. Pain behaviors at different time points were assessed by ambulatory pain scores and paw withdrawal mechanical threshold (PWMT). Pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, IL-18, and tumor necrosis factor alpha (TNF-α), were quantitated by Western blots. Glial activity was assessed by immunohistochemistry. Intra-tibia inoculation of Walker 256 mammary gland carcinoma cells induced progressive bone cancer pain; a long-term up-regulation of IL-1β, IL-6, IL-18, and TNF-α; and the activation of glia in spinal cord. Activation of microglia was first evident on day 4 after surgery and reached to a peak on day 7 while activation of astrocytes was on day 10. A single intrathecal injection of JWH-015 attenuated bone cancer induced spontaneous pain and mechanical allodynia, reduced the expression of pro-inflammatory cytokines, and inhibited the activity of astrocytes. All the modifications were transient and peaked at 24 h after JWH-015 administration. Furthermore, the protective effects of JWH-015 were reversed in the presence of CB2-selective antagonist AM630. Overall, our results provided evidences for the persistent participation of inflammation reaction in the progression of bone cancer pain, and demonstrated that JWH-015 reduced the expression of IL-1β, IL-6, IL-18, and TNF-α and inhibited astrocytes activation in a time-dependent manner, thereby displaying an analgesic effect.