Division of Oral Physiology, Department of Oral Biological Science, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
PLoS One. 2012;7(9):e44023. doi: 10.1371/journal.pone.0044023. Epub 2012 Sep 4.
Increased expression of the transient receptor potential vanilloid 1 (TRPV1) channels, following nerve injury, may facilitate the entry of QX-314 into nociceptive neurons in order to achieve effective and selective pain relief. In this study we hypothesized that the level of QX-314/capsaicin (QX-CAP)--induced blockade of nocifensive behavior could be used as an indirect in-vivo measurement of functional expression of TRPV1 channels. We used the QX-CAP combination to monitor the functional expression of TRPV1 in regenerated neurons after inferior alveolar nerve (IAN) transection in rats. We evaluated the effect of this combination on pain threshold at different time points after IAN transection by analyzing the escape thresholds to mechanical stimulation of lateral mental skin. At 2 weeks after IAN transection, there was no QX-CAP mediated block of mechanical hyperalgesia, implying that there was no functional expression of TRPV1 channels. These results were confirmed immunohistochemically by staining of regenerated trigeminal ganglion (TG) neurons. This suggests that TRPV1 channel expression is an essential necessity for the QX-CAP mediated blockade. Furthermore, we show that 3 and 4 weeks after IAN transection, application of QX-CAP produced a gradual increase in escape threshold, which paralleled the increased levels of TRPV1 channels that were detected in regenerated TG neurons. Immunohistochemical analysis also revealed that non-myelinated neurons regenerated slowly compared to myelinated neurons following IAN transection. We also show that TRPV1 expression shifted towards myelinated neurons. Our findings suggest that nerve injury modulates the TRPV1 expression pattern in regenerated neurons and that the effectiveness of QX-CAP induced blockade depends on the availability of functional TRPV1 receptors in regenerated neurons. The results of this study also suggest that the QX-CAP based approach can be used as a new behavioral tool to detect dynamic changes in TRPV1 expression, in various pathological conditions.
在神经损伤后，瞬时受体电位香草酸 1（TRPV1）通道表达增加，可能有助于 QX-314 进入伤害感受神经元，从而实现有效和选择性的疼痛缓解。在这项研究中，我们假设 QX-314/辣椒素（QX-CAP）诱导的伤害性行为阻断的水平可以作为 TRPV1 通道功能表达的间接体内测量。我们使用 QX-CAP 组合来监测大鼠下牙槽神经（IAN）切断后再生神经元中 TRPV1 的功能表达。我们通过分析侧向颏皮机械刺激的逃避阈值，评估 IAN 切断后不同时间点该组合对疼痛阈值的影响。在 IAN 切断后 2 周，没有 QX-CAP 介导的机械性痛觉过敏阻断，这意味着没有 TRPV1 通道的功能表达。这些结果通过对再生三叉神经节（TG）神经元进行免疫组织化学染色得到了证实。这表明 TRPV1 通道表达是 QX-CAP 介导的阻断的必要条件。此外，我们表明，在 IAN 切断后 3 周和 4 周，QX-CAP 的应用导致逃避阈值逐渐增加，这与在再生 TG 神经元中检测到的 TRPV1 通道水平的增加平行。免疫组织化学分析还显示，与 IAN 切断后再生的有髓神经元相比，无髓神经元再生缓慢。我们还表明，TRPV1 表达向有髓神经元转移。我们的研究结果表明，神经损伤调节再生神经元中 TRPV1 的表达模式，并且 QX-CAP 诱导的阻断的有效性取决于再生神经元中功能性 TRPV1 受体的可用性。这项研究的结果还表明，基于 QX-CAP 的方法可以用作检测各种病理条件下 TRPV1 表达动态变化的新行为工具。
