Peripheral endothelin B receptor agonist-induced antinociception involves endogenous opioids in mice.
Peripheral endothelin B receptor agonist-induced antinociception involves endogenous opioids in mice.
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DOI：
10.1016/j.pain.2010.02.009
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发表时间：
2010-05
期刊：
影响因子：
7.4
通讯作者：
Schmidt BL
中科院分区：
文献类型：
--
作者：
Quang PN;Schmidt BL
众所周知，各种癌症产生的内皮素-1 (ET-1) 会引起疼痛。虽然 ET-1 与周围神经上的 ETAR 结合明显介导伤害感受，但与 ETBR 结合的影响尚不清楚。本研究使用原位癌痛小鼠模型评估了 ETBR 激活的效果以及内源性阿片类药物镇痛在癌痛中的作用。 mRNA 表达分析显示，与正常口腔角质形成细胞 (NOK) 相比，人口腔 SCC 细胞系中 ET-1 几乎加倍，而 ETBR 显着下调。用 ETBR 激动剂（10−4M、10−5 M 和 10−6 M BQ-3020）处理的鳞状细胞癌 (SCC) 细胞培养物显着增加 β-内啡肽的产生，而对亮氨酸脑啡肽或强啡肽没有任何影响。与假注射组和注射 NOK 的组相比，在患有 SCC 的无胸腺小鼠的后爪中接种癌症会引起明显的疼痛，这通过响应机械刺激的缩爪阈值降低而表明。与 PBS 载体和对侧注射相比，肿瘤内注射 3 mg/kg BQ-3020 可在注射后 3 小时内减轻约 50% 的癌症疼痛，而肿瘤内 ETBR 拮抗剂 BQ-788 治疗（100 和 300 μg/kg 和 3 mg/kg）则没有效果。局部注射纳洛酮甲碘 (500 μg/kg) 或选择性 μ-阿片受体拮抗剂 (CTOP, 500 μg/kg) 可逆转癌症动物中 ETBR 激动剂诱导的镇痛作用。我们认为这些结果证明外周 ETBR 激动剂通过调节 SCC 释放的 β-内啡肽作用于癌症微环境中发现的外周阿片受体来减轻癌痛。
Endothelin-1 (ET-1) produced by various cancers is known to be responsible for inducing pain. While ET-1 binding to ETAR on peripheral nerves clearly mediates nociception, effects from binding to ETBR are less clear. The present study assessed the effects of ETBR activation and the role of endogenous opioid analgesia in carcinoma pain using an orthotopic cancer pain mouse model. mRNA expression analysis showed that ET-1 was nearly doubled while ETBR was significantly down-regulated in a human oral SCC cell line compared to normal oral keratinocytes (NOK). Squamous cell carcinoma (SCC) cell culture treated with an ETBR agonist (10−4M, 10−5 M, and 10−6 M BQ-3020) significantly increased production of β-endorphin without any effects on leu-enkephalin or dynorphin. Cancer inoculated in the hind paw of athymic mice with SCC induced significant pain, as indicated by reduction of paw withdrawal thresholds in response to mechanical stimulation, compared to sham-injected and NOK-injected groups. Intratumor administration of 3 mg/kg BQ-3020 attenuated cancer pain by approximately 50% up to 3 hours post-injection compared to PBS-vehicle and contralateral injection, while intratumor ETBR antagonist BQ-788 treatment (100 and 300 μg/kg and 3 mg/kg) had no effects. Local naloxone methiodide (500 μg/kg) or selective μ-opioid receptor antagonist (CTOP, 500 μg/kg) injection reversed ETBR agonist-induced antinociception in cancer animals. We propose that these results demonstrate that peripheral ETBR agonism attenuates carcinoma pain by modulating β-endorphins released from the SCC to act on peripheral opioid receptors found in the cancer microenvironment.
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