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Toll-like receptor 4 signaling in trigeminal ganglion neurons contributes tongue-referred pain associated with tooth pulp inflammation.

Ohara K, Shimizu K, Matsuura S, Ogiso B, Omagari D, Asano M, Tsuboi Y, Shinoda M, Iwata K - J Neuroinflammation (2013)

Bottom Line: The purpose of the present study is to evaluate the mechanisms underlying tongue-referred pain associated with tooth pulp inflammation.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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Endodontics, Nihon University School of Dentistry, 1-8-13 Kandasurugadai, Chiyoda-ku, Tokyo 101-8310, Japan. shimizu.kouhei01@nihon-u.ac.jp.

ABSTRACT

Background: The purpose of the present study is to evaluate the mechanisms underlying tongue-referred pain associated with tooth pulp inflammation.

Method: 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.

Results: 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.

Conclusions: 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.

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HWT to mechanical or heat stimulation of the tongue in pulpal Hsp70-, LPS-applied, or sham rats, and the effect of LPS blocker LPS-RS on HWT. A, B: HWT to mechanical (A) and heat stimulation (B) of the tongue in pulpal Hsp70-applied rats or sham rats. C, D: HWT to mechanical (C) and heat stimulation (D) of the tongue in pulpal LPS-applied rats or sham rats. E, F: Change in HWT to mechanical (E) and heat stimulation (F) of the tongue following TG injection of LPS-RS or vehicle in pulpal CFA-applied rats. ***, ###: P < 0.001.
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Figure 4: HWT to mechanical or heat stimulation of the tongue in pulpal Hsp70-, LPS-applied, or sham rats, and the effect of LPS blocker LPS-RS on HWT. A, B: HWT to mechanical (A) and heat stimulation (B) of the tongue in pulpal Hsp70-applied rats or sham rats. C, D: HWT to mechanical (C) and heat stimulation (D) of the tongue in pulpal LPS-applied rats or sham rats. E, F: Change in HWT to mechanical (E) and heat stimulation (F) of the tongue following TG injection of LPS-RS or vehicle in pulpal CFA-applied rats. ***, ###: P < 0.001.

Mentions: Three days after recombinant Hsp70 application to the M1TP in naive rats, the HWTs to mechanical and heat stimulation of the tongue were significantly decreased compared with that of saline-applied rats (P <0.001, n = 5 in each group) (Figure 4A and B).


Toll-like receptor 4 signaling in trigeminal ganglion neurons contributes tongue-referred pain associated with tooth pulp inflammation.

Ohara K, Shimizu K, Matsuura S, Ogiso B, Omagari D, Asano M, Tsuboi Y, Shinoda M, Iwata K - J Neuroinflammation (2013)

HWT to mechanical or heat stimulation of the tongue in pulpal Hsp70-, LPS-applied, or sham rats, and the effect of LPS blocker LPS-RS on HWT. A, B: HWT to mechanical (A) and heat stimulation (B) of the tongue in pulpal Hsp70-applied rats or sham rats. C, D: HWT to mechanical (C) and heat stimulation (D) of the tongue in pulpal LPS-applied rats or sham rats. E, F: Change in HWT to mechanical (E) and heat stimulation (F) of the tongue following TG injection of LPS-RS or vehicle in pulpal CFA-applied rats. ***, ###: P < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4222866&req=5

Figure 4: HWT to mechanical or heat stimulation of the tongue in pulpal Hsp70-, LPS-applied, or sham rats, and the effect of LPS blocker LPS-RS on HWT. A, B: HWT to mechanical (A) and heat stimulation (B) of the tongue in pulpal Hsp70-applied rats or sham rats. C, D: HWT to mechanical (C) and heat stimulation (D) of the tongue in pulpal LPS-applied rats or sham rats. E, F: Change in HWT to mechanical (E) and heat stimulation (F) of the tongue following TG injection of LPS-RS or vehicle in pulpal CFA-applied rats. ***, ###: P < 0.001.
Mentions: Three days after recombinant Hsp70 application to the M1TP in naive rats, the HWTs to mechanical and heat stimulation of the tongue were significantly decreased compared with that of saline-applied rats (P <0.001, n = 5 in each group) (Figure 4A and B).

Bottom Line: The purpose of the present study is to evaluate the mechanisms underlying tongue-referred pain associated with tooth pulp inflammation.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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Endodontics, Nihon University School of Dentistry, 1-8-13 Kandasurugadai, Chiyoda-ku, Tokyo 101-8310, Japan. shimizu.kouhei01@nihon-u.ac.jp.

ABSTRACT

Background: The purpose of the present study is to evaluate the mechanisms underlying tongue-referred pain associated with tooth pulp inflammation.

Method: 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.

Results: 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.

Conclusions: 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.

Show MeSH
Related in: MedlinePlus