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首页> 外文期刊>The European Journal of Neuroscience >P2X receptors in sensory neurons co-cultured with cancer cells exhibit a decrease in opioid sensitivity.
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P2X receptors in sensory neurons co-cultured with cancer cells exhibit a decrease in opioid sensitivity.

机译：与癌细胞共培养的感觉神经元中的P2X受体显示出阿片类药物敏感性降低。

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Opioids are known to control the activity of P2X receptors in the sensory neurons of rats. These receptors are important in persistent pain signaling. However, there are extremely severe pain states, such as those associated with metastatic diseases, that are refractory to opioid treatment. We have tested the possibility that cancer cells affect the sensitivity of P2X(2/3) and P2X(2) receptors to opiates. The sensitivity of ATP-activated currents to the selective mu-opioid receptor agonist endomorphin-1 was evaluated in rat nodose neurons co-cultured (on separate coverslips) with fibrosarcoma cells (NCTC 2472) using whole-cell patch-clamp recordings. Both in control and in co-cultured neurons, P2X-mediated responses exhibited highly variable biphasic desensitization kinetics with fast and slow components. However, ATP-activated currents in co-cultured neurons acquired a new feature: the degree of their inhibition by endomorphin-1 demonstrated strong dependence on their desensitization kinetics. The neurons with 'slower' responses were subject to a smaller inhibitory effect of the opioid. The 'ultra-slow' responses completely lost their sensitivity to the opioid. The occurrence of such responses, rarely observed in the control neurons, was considerably increased with the duration of co-culturing. Application of endomorphin-1 to nodose neurons, co-cultured with rapidly proliferating but non-malignant cells (fibroblasts), resulted in data similar to those for the control. In summary, fibrosarcoma cells release diffusible factors altering the properties of desensitization kinetics of P2X receptors and, in particular, decrease their sensitivity to opioid inhibitory control. These phenomena may increase neuronal excitability initiated by peripheral ATP release and thereby contribute to the decreased sensitivity of cancer pain to opioids.
机译：已知阿片样物质可控制大鼠感觉神经元中P2X受体的活性。这些受体在持续的疼痛信号传导中很重要。然而，存在阿片类药物治疗难以治疗的极其严重的疼痛状态，例如与转移性疾病相关的疼痛状态。我们已经测试了癌细胞影响P2X（2/3）和P2X（2）受体对阿片类药物的敏感性的可能性。使用全细胞膜片钳记录，在与纤维肉瘤细胞（NCTC 2472）共培养（在单独的盖玻片上）的大鼠结节神经元中，评估了ATP激活电流对选择性mu阿片受体激动剂endomorphin-1的敏感性。无论是在控制神经元还是在共培养的神经元中，P2X介导的反应都表现出高度可变的双相脱敏动力学，具有快速和缓慢的成分。但是，共培养神经元中的ATP激活电流具有一个新功能：内啡肽1对它们的抑制程度强烈依赖于它们的脱敏动力学。具有“较慢”反应的神经元受到阿片样物质较小的抑制作用。 “超慢”反应完全失去了对阿片类药物的敏感性。随着共培养的持续时间，在对照神经元中很少观察到的这种反应的发生率显着增加。将内啡肽1应用于与快速增殖但非恶性细胞（成纤维细胞）共培养的结节神经元，得到的数据与对照相似。总之，纤维肉瘤细胞释放可扩散因子，改变P2X受体脱敏动力学的特性，特别是降低其对阿片样物质抑制控制的敏感性。这些现象可能会增加外围ATP释放引发的神经元兴奋性，从而导致癌症疼痛对阿片类药物的敏感性降低。

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