Differential effects of peripheral versus central coadministration of QX-314 and capsaicin on neuropathic pain in rats.
Differential effects of peripheral versus central coadministration of QX-314 and capsaicin on neuropathic pain in rats.
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DOI：
10.1097/aln.0b013e318260de41
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发表时间：
2012-08
期刊：
影响因子：
8.8
通讯作者：
Cheng J
中科院分区：
文献类型：
--
作者：
Shen J;Fox LE;Cheng J
神经病理性疼痛是常见且难以治疗的。最近开发了一种通过同时应用两种药物来选择性抑制伤害性输入的技术：辣椒素，一种瞬时受体电位香草酸受体1通道激活剂和QX-314，一种利多卡因衍生物，其在细胞内阻断钠通道。我们用这种技术来研究瞬时受体电位香草酸受体1表达的伤害感受器是否有助于神经病理性疼痛。使用大鼠慢性压迫性损伤模型诱导神经性疼痛，以测试外周（坐骨周）和中枢（鞘内）施用QX-314/辣椒素组合的镇痛作用。Hargreaves和von Frey试验用于监测诱发的疼痛样行为，视觉观察用于对自发性疼痛样行为进行分级。在具有神经损伤的大鼠（n = 6/组）中，QX-314/辣椒素组合的坐骨神经周围注射使机械和热刺激的退缩阈值瞬时增加约3倍，表明外周瞬时受体电位香草酸受体1表达伤害感受器有助于神经性疼痛。相比之下，鞘内施用QX-314/辣椒素组合没有减轻疼痛样行为（n = 5/组）。令人惊讶的是，鞘内QX-314单独（n = 9）或与辣椒素组合（n = 8）诱发自发性疼痛样行为。来自坐骨神经周围注射的数据表明，神经性疼痛的一个组成部分是由外周伤害性输入介导的。由于鞘内药物联合给药的严重副作用，中枢伤害性末梢的作用无法确定。我们的结论是，只有外周阻断瞬时受体电位香草酸受体1表达的伤害性传入的QX-314/辣椒素组合是有效的，在减少神经性异常性疼痛和痛觉过敏。
Neuropathic pain is common and difficult to treat. Recently a technique was developed to selectively inhibit nociceptive inputs by simultaneously applying two drugs: capsaicin, a transient receptor potential vanilloid receptor 1 channel activator and QX-314, a lidocaine derivative that intracellularly blocks sodium channels. We used this technique to investigate whether transient receptor potential vanilloid receptor 1-expressing nociceptors contribute to neuropathic pain. The rat chronic constriction injury model was used to induce neuropathic pain in order to test the analgesic effects of both peripheral (perisciatic) and central (intrathecal) administration of the QX-314/capsaicin combination. The Hargreaves and von Frey tests were used to monitor evoked pain-like behaviors and visual observations were used to rank spontaneous pain-like behaviors. Perisciatic injections of the QX-314/capsaicin combination transiently increased the withdrawal thresholds by ~3 fold for mechanical and thermal stimuli in rats (n = 6/group) with nerve injuries suggesting that peripheral transient receptor potential vanilloid receptor 1-expressing nociceptors contribute to neuropathic pain. In contrast, intrathecal administration of the QX-314/capsaicin combination did not alleviate pain-like behaviors (n = 5/group). Surprisingly, intrathecal QX-314 alone (n = 9) or in combination with capsaicin (n = 8) evoked spontaneous pain-like behaviors. Data from the perisciatic injections suggested that a component of neuropathic pain was mediated by peripheral nociceptive inputs. The role of central nociceptive terminals could not be determined because of the severe side effects of the intrathecal drug combination. We concluded that only peripheral blockade of transient receptor potential vanilloid receptor 1-expressing nociceptive afferents by the QX-314/capsaicin combination was effective at reducing neuropathic allodynia and hyperalgesia.