New insights into mechanisms of opioid inhibitory effects on capsaicin-induced TRPV1 activity during painful diabetic neuropathy
New insights into mechanisms of opioid inhibitory effects on capsaicin-induced TRPV1 activity during painful diabetic neuropathy
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DOI：
10.1016/j.neuropharm.2014.05.026
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发表时间：
2014-10
影响因子：
4.7
通讯作者：
M. Shaqura;Baled I. Khalefa;M. Shakibaei;C. Zöllner;M. Al-Khrasani;S. Fürst;M. Schäfer;S. Mousa
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文献类型：
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作者：
M. Shaqura;Baled I. Khalefa;M. Shakibaei;C. Zöllner;M. Al-Khrasani;S. Fürst;M. Schäfer;S. Mousa
疼痛性糖尿病神经病是一种外周感觉神经元阿片反应性受损的疾病。由于μ-阿片受体（MOR）激活可抑制外周感觉神经元瞬时受体电位香草样蛋白1 （TRPV1）活性，本研究探讨了疼痛性糖尿病神经病变中阿片抑制作用受损对辣椒素诱导的TRPV1活性的影响机制。Wistar大鼠静脉注射链脲佐菌素（STZ, 45 mg/kg）可导致产生胰岛素的胰腺β细胞变性、血糖升高和机械性超敏反应（异常性疼痛）。在这些动物中，局部吗啡对辣椒素诱导的攻击行为和辣椒素诱导的背根神经节细胞TRPV1电流的抑制作用明显受损。这些变化与MOR的丧失有关，但与外周感觉神经元TRPV1的丧失无关。在糖尿病动物鞘内注入神经生长因子使感觉神经元MOR正常化，随后恢复吗啡对辣椒素诱导的TRPV1活性的抑制作用。这些发现表明，在stz诱导的晚期糖尿病中，感觉神经元功能性MOR的丧失是阿片样物质对辣椒素诱导的TRPV1活性抑制作用受损的一个因素。此外，它们支持越来越多的证据表明，在各种疾病疼痛状态（如关节炎、癌症、神经病变）中，阿片类药物反应性有明显的调节，并可能提供新的治疗激励。
Painful diabetic neuropathy is a disease of the peripheral sensory neuron with impaired opioid responsiveness. Since μ-opioid receptor (MOR) activation can inhibit the transient receptor potential vanilloid 1 (TRPV1) activity in peripherally sensory neurons, this study investigated the mechanisms of impaired opioid inhibitory effects on capsaicin-induced TRPV1 activity in painful diabetic neuropathy. Intravenous injection of streptozotocin (STZ, 45 mg/kg) in Wistar rats led to a degeneration of insulin producing pancreatic β-cells, elevated blood glucose, and mechanical hypersensitivity (allodynia). In these animals, local morphine's inhibitory effects on capsaicin-induced nocifensive behavior as well as on capsaicin-induced TRPV1 current in dorsal root ganglion cells were significantly impaired. These changes were associated with a loss in MOR but not TRPV1 in peripheral sensory neurons. Intrathecal delivery of nerve growth factor in diabetic animals normalized sensory neuron MOR and subsequently rescued morphine's inhibitory effects on capsaicin-induced TRPV1 activityin vivoandin vitro. These findings identify a loss in functional MOR on sensory neurons as a contributing factor for the impaired opioid inhibitory effects on capsaicin-induced TRPV1 activity during advanced STZ-induced diabetes. Moreover, they support growing evidence of a distinct regulation of opioid responsiveness during various painful states of disease (e.g. arthritis, cancer, neuropathy) and may give novel therapeutic incentives.