Endothelin-A receptor antagonism attenuates carcinoma-induced pain through opioids in mice.
Endothelin-A receptor antagonism attenuates carcinoma-induced pain through opioids in mice.
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DOI：
10.1016/j.jpain.2009.10.011
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发表时间：
2010-07
期刊：
影响因子：
--
通讯作者：
Schmidt BL
中科院分区：
文献类型：
--
作者：
Quang PN;Schmidt BL
我们先前报道内皮素A(ET-A)受体拮抗剂可以减轻癌痛小鼠模型中的癌痛。在本研究中，我们探讨了ET-A受体介导的抗伤害性作用的机制，并评价了内源性阿片类镇痛的作用。ET-A受体拮抗剂(BQ-123)在10−6M和10−5M作用于鳞状细胞癌细胞，可显著增加β-内啡肽和亮氨酸脑啡肽的产生和分泌。通过局部注射人口腔鳞状细胞癌来源的细胞在雌性裸鼠后爪诱发肿瘤，进行了行为学研究。显著的疼痛，如对机械刺激反应的戒断阈值的降低，从接种鳞状细胞癌后的4天开始，持续到测量的最后一天-18天。在肿瘤动物体内局部应用选择性的µ-阿片受体拮抗剂(500µg/kg)或δ-阿片受体拮抗剂(11 mg/kg)，但不给予κ-阿片受体拮抗剂(Nor-BNI2.5 mg/kg)，均能显著逆转ET-A受体拮抗剂(BQ-123，92 mg/kg)的抗伤害性作用。这些结果表明，外周内皮素-A受体的拮抗作用是通过调节内源性阿片类药物的释放作用于癌症微环境中的阿片受体来减轻癌症疼痛的。
We previously reported that endothelin A (ET-A) receptor antagonism attenuates carcinoma-induced pain in a cancer pain mouse model. In this study, we investigated the mechanism of ET-A receptor-mediated antinociception and evaluated the role of endogenous opioid analgesia. Squamous cell carcinoma (SCC) cell culture treated with the ET-A receptor antagonist (BQ-123) at 10−6 M and 10−5 M significantly increased production and secretion of β-endorphin and leu-enkephalin, respectively. Behavioral studies were performed by inducing tumors in the hind paw of female nude mice with local injection of cells derived from a human oral SCC. Significant pain, as indicated by reduction in withdrawal thresholds in response to mechanical stimulation, began at four days after SCC inoculation and lasted to 18 days, the last day of measurement. Local administration of either naloxone methiodide (500 µg/kg), selective antagonists for µ-opioid receptor (CTOP, 500 µg/kg) or δ-opioid receptor (naltrindole, 11 mg/kg), but not κ-opioid receptor (nor-BNI, 2.5 mg/kg), significantly reversed antinociception observed from ET-A receptor antagonism (BQ-123, 92 mg/kg) in cancer animals. These results demonstrate that antagonism of peripheral endothelin-A receptor attenuates carcinoma pain by modulating release of endogenous opioids to act on opioid receptors in the cancer microenvironment.
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影响因子：
4.9
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