Zhou Ya-Qun, Chen Shu-Ping, Liu Dai-Qiang, Manyande Anne, Zhang Wen, Yang Shao-Bing, Xiong Bing-Rui, Fu Qiao-Chu, Song Zhen-Peng, Rittner Heike, Ye Da-Wei, Tian Yu-Ke
Anesthesiology Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
School of Human and Social Sciences, University of West London, London, UK.
J Pain. 2017 Aug;18(8):933-946. doi: 10.1016/j.jpain.2017.02.438. Epub 2017 Mar 18.
Cancer-induced bone pain (CIBP) remains a major challenge in advanced cancer patients because of our lack of understanding of its mechanisms. Previous studies have shown the vital role of γ-aminobutyric acid B receptors (GABABRs) in regulating nociception and various neuropathic pain models have shown diminished activity of GABABRs. However, the role of spinal GABABRs in CIBP remains largely unknown. In this study, we investigated the specific cellular mechanisms of GABABRs in the development and maintenance of CIBP in rats. Our behavioral results show that acute as well as chronic intrathecal treatment with baclofen, a GABABR agonist, significantly attenuated CIBP-induced mechanical allodynia and ambulatory pain. The expression levels of GABABRs were significantly decreased in a time-dependent manner and colocalized mostly with neurons and a minority with astrocytes and microglia. Chronic treatment with baclofen restored the expression of GABABRs and markedly inhibited the activation of cyclic adenosine monophosphate (cAMP)-dependent protein kinase and the cAMP-response element-binding protein signaling pathway.
Our findings provide, to our knowledge, the first evidence that downregulation of GABABRs contribute to the development and maintenance of CIBP and restored diminished GABABRs attenuate CIBP-induced pain behaviors at least partially by inhibiting the protein kinase/cAMP-response element-binding protein signaling pathway. Therefore, spinal GABABR may become a potential therapeutic target for the management of CIBP.
由于我们对癌症诱发的骨痛（CIBP）机制缺乏了解，它仍然是晚期癌症患者面临的一项重大挑战。先前的研究表明，γ-氨基丁酸B受体（GABABRs）在调节伤害感受中起着至关重要的作用，并且各种神经病理性疼痛模型显示GABABRs的活性降低。然而，脊髓GABABRs在CIBP中的作用在很大程度上仍然未知。在本研究中，我们调查了GABABRs在大鼠CIBP发生和维持中的具体细胞机制。我们的行为学结果表明，用GABABR激动剂巴氯芬进行急性和慢性鞘内注射治疗，可显著减轻CIBP诱导的机械性异常性疼痛和动态性疼痛。GABABRs的表达水平以时间依赖性方式显著降低，并且主要与神经元共定位，少数与星形胶质细胞和小胶质细胞共定位。巴氯芬的慢性治疗恢复了GABABRs的表达，并显著抑制了环磷酸腺苷（cAMP）依赖性蛋白激酶和cAMP反应元件结合蛋白信号通路的激活。
据我们所知，我们的研究结果首次证明GABABRs的下调促成了CIBP的发生和维持，而恢复降低的GABABRs至少部分地通过抑制蛋白激酶/cAMP反应元件结合蛋白信号通路来减轻CIBP诱导的疼痛行为。因此，脊髓GABABR可能成为治疗CIBP的潜在靶点。
