Toll-like Receptor 4 Signaling in Trigeminal Ganglion Neurons Contributes Tongue-referred Pain Associated with Tooth Pulp Inflammation

Overview

Journal J Neuroinflammation

Publisher Biomed Central

Date 2013 Nov 26

PMID 24267924

Citations 19

Authors

Kinuyo Ohara

Kohei Shimizu

Shingo Matsuura

Bunnai Ogiso

Daisuke Omagari

Masatake Asano

Yoshiyuki Tsuboi

Masamichi Shinoda

Koichi Iwata

Affiliations

Soon will be listed here.

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.

Citing Articles

Sensory neuronal control of skin barrier immunity.

Feng X, Zhan H, Sokol C Trends Immunol. 2024; 45(5):371-380.

PMID: 38653601 PMC: 11102800. DOI: 10.1016/j.it.2024.03.008.

Lipopolysaccharide-induced Trigeminal Ganglion Nerve Fiber Damage is Associated with Autophagy Inhibition.

Li Y, Li J, Wei S, Du J Curr Med Sci. 2023; 43(3):489-495.

PMID: 37278832 DOI: 10.1007/s11596-023-2739-0.

Genetic variants at the locus are associated with fatigue in Scandinavian patients with primary Sjögren's syndrome.

Norheim K, Imgenberg-Kreuz J, Alexsson A, Johnsen S, Bardsen K, Brun J RMD Open. 2021; 7(3.

PMID: 34907023 PMC: 8671987. DOI: 10.1136/rmdopen-2021-001832.

Upregulation of Toll-like Receptor 2 in Dental Primary Afferents Following Pulp Injury.

Lee P, Lee J, Park J, Oh S Exp Neurobiol. 2021; 30(5):329-340.

PMID: 34737238 PMC: 8572661. DOI: 10.5607/en21018.

Role of macrophage-mediated Toll-like receptor 4-interleukin-1R signaling in ectopic tongue pain associated with tooth pulp inflammation.

Kanno K, Shimizu K, Shinoda M, Hayashi M, Takeichi O, Iwata K J Neuroinflammation. 2020; 17(1):312.

PMID: 33081813 PMC: 7576725. DOI: 10.1186/s12974-020-01995-y.

References

BENDER I . Pulpal pain diagnosis--a review. J Endod. 2001; 26(3):175-9. DOI: 10.1097/00004770-200003000-00012. View

Turturici G, Sconzo G, Geraci F . Hsp70 and its molecular role in nervous system diseases. Biochem Res Int. 2011; 2011:618127. PMC: 3049350. DOI: 10.1155/2011/618127. View

Giffard R, Han R, Emery J, Duan M, Pittet J . Regulation of apoptotic and inflammatory cell signaling in cerebral ischemia: the complex roles of heat shock protein 70. Anesthesiology. 2008; 109(2):339-48. PMC: 2561962. DOI: 10.1097/ALN.0b013e31817f4ce0. View

Okun E, Griffioen K, Mattson M . Toll-like receptor signaling in neural plasticity and disease. Trends Neurosci. 2011; 34(5):269-81. PMC: 3095763. DOI: 10.1016/j.tins.2011.02.005. View

Liu T, Gao Y, Ji R . Emerging role of Toll-like receptors in the control of pain and itch. Neurosci Bull. 2012; 28(2):131-44. PMC: 3347759. DOI: 10.1007/s12264-012-1219-5. View

Kim J, Yenari M . The immune modulating properties of the heat shock proteins after brain injury. Anat Cell Biol. 2013; 46(1):1-7. PMC: 3615608. DOI: 10.5115/acb.2013.46.1.1. View

Zimmermann M . Ethical guidelines for investigations of experimental pain in conscious animals. Pain. 1983; 16(2):109-110. DOI: 10.1016/0304-3959(83)90201-4. View

Katagiri A, Shinoda M, Honda K, Toyofuku A, Sessle B, Iwata K . Satellite glial cell P2Y12 receptor in the trigeminal ganglion is involved in lingual neuropathic pain mechanisms in rats. Mol Pain. 2012; 8:23. PMC: 3386019. DOI: 10.1186/1744-8069-8-23. View

Shinoda M, Asano M, Omagari D, Honda K, Hitomi S, Katagiri A . Nerve growth factor contribution via transient receptor potential vanilloid 1 to ectopic orofacial pain. J Neurosci. 2011; 31(19):7145-55. PMC: 6703199. DOI: 10.1523/JNEUROSCI.0481-11.2011. View

10.

Ji R . Peripheral and central mechanisms of inflammatory pain, with emphasis on MAP kinases. Curr Drug Targets Inflamm Allergy. 2004; 3(3):299-303. DOI: 10.2174/1568010043343804. View

11.

Yasuda M, Shinoda M, Kiyomoto M, Honda K, Suzuki A, Tamagawa T . P2X3 receptor mediates ectopic mechanical allodynia with inflamed lower lip in mice. Neurosci Lett. 2012; 528(1):67-72. DOI: 10.1016/j.neulet.2012.08.067. View

12.

Diogenes A, Ferraz C, Akopian A, Henry M, Hargreaves K . LPS sensitizes TRPV1 via activation of TLR4 in trigeminal sensory neurons. J Dent Res. 2011; 90(6):759-64. DOI: 10.1177/0022034511400225. View

13.

Ertekin C, Secil Y, Yuceyar N, Aydogdu I . Oropharyngeal dysphagia in polymyositis/dermatomyositis. Clin Neurol Neurosurg. 2004; 107(1):32-7. DOI: 10.1016/j.clineuro.2004.02.024. View

14.

Zhang Y, Wang Y, Zhang X, Ge H, Arendt-Nielsen L, Shao J . Proteomic analysis of differential proteins related to the neuropathic pain and neuroprotection in the dorsal root ganglion following its chronic compression in rats. Exp Brain Res. 2008; 189(2):199-209. DOI: 10.1007/s00221-008-1419-4. View

15.

Pileggi R, Holland G . The expression of heat shock protein 70 in the dental pulp following trauma. Dent Traumatol. 2009; 25(4):426-8. DOI: 10.1111/j.1600-9657.2009.00801.x. View

16.

Omagari D, Takenouchi-Ohkubo N, Endo S, Ishigami T, Sawada A, Moro I . Nuclear factor kappa B plays a pivotal role in polyinosinic-polycytidylic acid-induced expression of human β-defensin 2 in intestinal epithelial cells. Clin Exp Immunol. 2011; 165(1):85-93. PMC: 3110324. DOI: 10.1111/j.1365-2249.2011.04404.x. View

17.

Ferraz C, Henry M, Hargreaves K, Diogenes A . Lipopolysaccharide from Porphyromonas gingivalis sensitizes capsaicin-sensitive nociceptors. J Endod. 2010; 37(1):45-8. PMC: 3032989. DOI: 10.1016/j.joen.2007.07.001. View

18.

Qi J, Buzas K, Fan H, Cohen J, Wang K, Mont E . Painful pathways induced by TLR stimulation of dorsal root ganglion neurons. J Immunol. 2011; 186(11):6417-26. PMC: 3098909. DOI: 10.4049/jimmunol.1001241. View

19.

Iguchi M, Littmann A, Chang S, Wester L, Knipper J, Shields R . Heat stress and cardiovascular, hormonal, and heat shock proteins in humans. J Athl Train. 2012; 47(2):184-90. PMC: 3418130. DOI: 10.4085/1062-6050-47.2.184. View

20.

Guo L, Schluesener H . The innate immunity of the central nervous system in chronic pain: the role of Toll-like receptors. Cell Mol Life Sci. 2007; 64(9):1128-36. PMC: 11136004. DOI: 10.1007/s00018-007-6494-3. View