Department of Endodontics, Nihon University School of Dentistry, 1-8-13 Kandasurugadai, Chiyoda-ku, Tokyo 101-8310, Japan.
J Neuroinflammation. 2013 Nov 23;10:139. doi: 10.1186/1742-2094-10-139.
The purpose of the present study is to evaluate the mechanisms underlying tongue-referred pain associated with tooth pulp inflammation.
Using mechanical and temperature stimulation following dental surgery, we have demonstrated that dental inflammation and hyperalgesia correlates with increased immunohistochemical staining of neurons for TLR4 and HSP70.
Mechanical or heat hyperalgesia significantly enhanced in the ipsilateral tongue at 1 to 9 days after complete Freund's adjuvant (CFA) application to the left lower molar tooth pulp compared with that of sham-treated or vehicle-applied rats. The number of fluorogold (FG)-labeled TLR4-immunoreactive (IR) cells was significantly larger in CFA-applied rats compared with sham-treated or vehicle-applied rats to the molar tooth. The number of heat shock protein (Hsp) 70-IR neurons in trigeminal ganglion (TG) was significantly increased on day 3 after CFA application compared with sham-treated or vehicle-applied rats to the molar tooth. About 9.2% of TG neurons were labeled with DiI applied to the molar tooth and FG injected into the tongue, and 15.4% of TG neurons were labeled with FG injected into the tongue and Alexa-labeled Hsp70-IR applied to the tooth. Three days after Hsp70 or lipopolysaccharide (LPS) application to the tooth in naive rats, mechanical or heat hyperalgesia was significantly enhanced compared with that of saline-applied rats. Following successive LPS-RS, an antagonist of TLR4, administration to the TG for 3 days, the enhanced mechanical or heat hyperalgesia was significantly reversed compared with that of saline-injected rats. Noxious mechanical responses of TG neurons innervating the tongue were significantly higher in CFA-applied rats compare with sham rats to the tooth. Hsp70 mRNA levels of the tooth pulp and TG were not different between CFA-applied rats and sham rats.
The present findings indicate that Hsp70 transported from the tooth pulp to TG neurons or expressed in TG neurons is released from TG neurons innervating inflamed tooth pulp, and is taken by TG neurons innervating the tongue, suggesting that the Hsp70-TLR4 signaling in TG plays a pivotal role in tongue-referred pain associated with tooth pulp inflammation.
本研究旨在探讨牙髓炎症相关舌牵涉痛的机制。
采用牙手术后的机械和温度刺激，我们发现，牙髓炎症和痛觉过敏与 TLR4 和 HSP70 免疫阳性神经元的增加有关。
与假手术或 vehicle 处理的大鼠相比，在完全弗氏佐剂（CFA）应用于左下磨牙牙髓后 1 至 9 天，同侧舌的机械或热痛敏显著增强。与假手术或 vehicle 处理的大鼠相比，CFA 处理的大鼠中，氟金胺（FG）标记的 TLR4 免疫反应性（IR）细胞数量显著增加。在 CFA 处理后第 3 天，三叉神经节（TG）中的热休克蛋白（Hsp）70-IR 神经元数量明显增加，与假手术或 vehicle 处理的大鼠相比。用金胺（DiI）处理磨牙并将 FG 注入舌，约有 9.2%的 TG 神经元被标记；用 FG 注入舌并用 Alexa 标记的 Hsp70-IR 处理牙，约有 15.4%的 TG 神经元被标记。在未经处理的大鼠中，将 Hsp70 或脂多糖（LPS）应用于牙后 3 天，机械或热痛敏明显增强，与生理盐水处理的大鼠相比。在连续给予 LPS-RS（TLR4 拮抗剂）3 天后，对 TG 进行治疗，与生理盐水注射的大鼠相比，增强的机械或热痛敏明显逆转。与假手术大鼠相比，在 CFA 处理的大鼠中，支配舌的 TG 神经元的有害机械反应明显升高。牙牙髓和 TG 中的 Hsp70 mRNA 水平在 CFA 处理的大鼠和假手术大鼠之间没有差异。
本研究结果表明，从牙髓转运到 TG 神经元或在 TG 神经元中表达的 Hsp70 从支配炎性牙髓的 TG 神经元中释放出来，并被支配炎性牙髓的 TG 神经元摄取，提示 TG 中的 Hsp70-TLR4 信号在牙髓炎症相关的舌牵涉痛中起关键作用。
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