Advertisement
Basic Research| Volume 42, ISSUE 10, P1496-1502, October 2016

Capsaicin-sensitive Innervation Modulates the Development of Apical Periodontitis

Published:August 11, 2016DOI:https://doi.org/10.1016/j.joen.2016.06.009

      Highlights

      • Neonatal capsaicin treatment led to selective ablation of TRPV1 containing neurons.
      • Neonatal capsaicin treatment reduced peptidergic innervation content in the dental pulp.
      • Loss of peptidergic innervation resulted in early development of apical periodontitis.

      Abstract

      Introduction

      Nociceptive neurons play a critical role in the detection of stimuli evoking actual or potential tissue injury. In addition, they are involved in neurogenic inflammation by the peripheral release of neuropeptides such as calcitonin gene-related peptide (CGRP). The dental pulp and periradicular tissues are innervated by capsaicin-sensitive neurons known to release CGRP. However, the role of these capsaicin-sensitive neurons in the development of apical periodontitis is largely unknown. The aim of this study was to evaluate the contribution of peptidergic neurons to the development of apical periodontitis.

      Methods

      Neonatal Sprague-Dawley rats were injected with vehicle (control group) or a single subcutaneous capsaicin dose to cause the selective ablation of peptidergic neurons (neonatal capsaicin group). Ablation of capsaicin-sensitive neurons was verified with confocal microscopy, capsaicin-induced eye-wipe nocifensive behavior test, and by measurement of immunoreactive CGRP levels in the dental pulp. Five weeks after ablation, standardized pulp exposures were made in the mandibular left first molars. Mandibles were harvested at 7, 14, 21, and 28 days after pulp exposure and imaged with micro–computed tomography (μCT) to quantify apical lesion volume. Data were analyzed by using 2-way ANOVA analysis with Bonferroni post hoc test.

      Results

      Rats in the control group displayed a robust capsaicin-induced nocifensive behavior, which was nearly abolished in the neonatal capsaicin group. In addition, the neonatal capsaicin group showed a significant depletion of susceptible neurons and CGRP in the dental pulp compared with control. Importantly, micro–computed tomography analysis showed larger periradicular lesions at 7 and 14 days after pulp exposure in the neonatal capsaicin group when compared with control.

      Conclusions

      Results identify a protective role for capsaicin-sensitive neurons in the initial phase of apical periodontitis. Thus, interventions or disorders that alter activity of capsaicin-sensitive fibers are likely to alter the development of apical periodontitis.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of Endodontics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Kakehashi S.
        • Stanley H.R.
        • Fitzgerald R.J.
        The effects of surgical exposures of dental pulps in germ-free and conventional laboratory rats.
        Oral Surg Oral Med Oral Pathol. 1965; 20: 340-349
        • Sundqvist G.
        Taxonomy, ecology, and pathogenicity of the root canal flora.
        Oral Surg Oral Med Oral Pathol. 1994; 78: 522-530
        • Henry M.A.
        • Hargreaves K.M.
        Peripheral mechanisms of odontogenic pain.
        Dent Clin North Am. 2007; 51 (v): 19-44
        • Kawashima N.
        • Okiji T.
        • Kosaka T.
        • Suda H.
        Kinetics of macrophages and lymphoid cells during the development of experimentally induced periapical lesions in rat molars: a quantitative immunohistochemical study.
        J Endod. 1996; 22: 311-316
        • Tani N.
        • Kuchiba K.
        • Osada T.
        • et al.
        Effect of T-cell deficiency on the formation of periapical lesions in mice: histological comparison between periapical lesion formation in BALB/c and BALB/c nu/nu mice.
        J Endod. 1995; 21: 195-199
        • Toriya Y.
        • Hashiguchi I.
        • Maeda K.
        Immunohistochemical examination of the distribution of macrophages and CGRP-immunoreactive nerve fibers in induced rat periapical lesions.
        Endod Dent Traumatol. 1997; 13: 6-12
        • Yu S.M.
        • Stashenko P.
        Identification of inflammatory cells in developing rat periapical lesions.
        J Endod. 1987; 13: 535-540
        • Wang C.Y.
        • Stashenko P.
        Kinetics of bone-resorbing activity in developing periapical lesions.
        J Dent Res. 1991; 70: 1362-1366
        • Balto K.
        • Muller R.
        • Carrington D.C.
        • et al.
        Quantification of periapical bone destruction in mice by micro-computed tomography.
        J Dent Res. 2000; 79: 35-40
        • von Stechow D.
        • Balto K.
        • Stashenko P.
        • Muller R.
        Three-dimensional quantitation of periradicular bone destruction by micro-computed tomography.
        J Endod. 2003; 29: 252-256
        • Stashenko P.
        Role of immune cytokines in the pathogenesis of periapical lesions.
        Endod Dent Traumatol. 1990; 6: 89-96
        • Narhi M.V.
        • Antila M.K.
        Innervation of teeth: a review.
        Proc Finn Dent Soc. 1973; 69: 208-216
        • Byers M.R.
        Effects of inflammation on dental sensory nerves and vice versa.
        Proc Finn Dent Soc. 1992; 88 Suppl 1: 499-506
        • Taylor P.E.
        • Byers M.R.
        An immunocytochemical study of the morphological reaction of nerves containing calcitonin gene-related peptide to microabscess formation and healing in rat molars.
        Arch Oral Biol. 1990; 35: 629-638
        • Kvinnsland I.
        • Heyeraas K.J.
        • Byers M.R.
        Effects of dental trauma on pulpal and periodontal nerve morphology.
        Proc Finn Dent Soc. 1992; 88 Suppl 1: 125-132
        • Byers M.R.
        • Swift M.L.
        • Wheeler E.F.
        Reactions of sensory nerves to dental restorative procedures.
        Proc Finn Dent Soc. 1992; 88 Suppl 1: 73-82
        • Fehrenbacher J.C.
        • Sun X.X.
        • Locke E.E.
        • et al.
        Capsaicin-evoked iCGRP release from human dental pulp: a model system for the study of peripheral neuropeptide secretion in normal healthy tissue.
        Pain. 2009; 144: 253-261
        • Goodis H.E.
        • Poon A.
        • Hargreaves K.M.
        Tissue pH and temperature regulate pulpal nociceptors.
        J Dent Res. 2006; 85: 1046-1049
        • Holzer P.
        Neurogenic vasodilatation and plasma leakage in the skin.
        Gen Pharmacol. 1998; 30: 5-11
        • Jancso N.
        • Jancso-Gabor A.
        • Szolcsanyi J.
        Direct evidence for neurogenic inflammation and its prevention by denervation and by pretreatment with capsaicin.
        Br J Pharmacol Chemother. 1967; 31: 138-151
        • Caterina M.J.
        • Schumacher M.A.
        • Tominaga M.
        • et al.
        The capsaicin receptor: a heat-activated ion channel in the pain pathway.
        Nature. 1997; 389: 816-824
        • Surh Y.J.
        • Lee S.S.
        Capsaicin, a double-edged sword: toxicity, metabolism, and chemopreventive potential.
        Life Sci. 1995; 56: 1845-1855
        • Tender G.C.
        • Walbridge S.
        • Olah Z.
        • et al.
        Selective ablation of nociceptive neurons for elimination of hyperalgesia and neurogenic inflammation.
        J Neurosurg. 2005; 102: 522-525
        • Hammond D.L.
        • Ruda M.A.
        Developmental alterations in nociceptive threshold, immunoreactive calcitonin gene-related peptide and substance P, and fluoride-resistant acid phosphatase in neonatally capsaicin-treated rats.
        J Comp Neurol. 1991; 312: 436-450
        • Nagy J.I.
        • Iversen L.L.
        • Goedert M.
        • et al.
        Dose-dependent effects of capsaicin on primary sensory neurons in the neonatal rat.
        J Neurosci. 1983; 3: 399-406
        • Szolcsanyi J.
        • Jancso-Gabor A.
        • Joo F.
        Functional and fine structural characteristics of the sensory neuron blocking effect of capsaicin.
        Naunyn Schmiedebergs Arch Pharmacol. 1975; 287: 157-169
        • He Y.F.
        • Ichikawa H.
        • Sugimoto T.
        The effect of neonatal capsaicin on the c-Fos-like immunoreactivity induced in subnucleus oralis neurons by noxious intraoral stimulation.
        Brain Res. 2000; 860: 203-207
        • Liu M.
        • Pertl C.
        • Markowitz K.
        • et al.
        The effects of capsaicin on pulpal blood flow.
        Proc Finn Dent Soc. 1992; 88 Suppl 1: 463-467
        • Ichikawa H.
        • Sugimoto T.
        VR1-immunoreactive primary sensory neurons in the rat trigeminal ganglion.
        Brain Res. 2001; 890: 184-188
        • Caterina M.J.
        • Leffler A.
        • Malmberg A.B.
        • et al.
        Impaired nociception and pain sensation in mice lacking the capsaicin receptor.
        Science. 2000; 288: 306-313
        • Morgan C.R.
        • Rodd H.D.
        • Clayton N.
        • et al.
        Vanilloid receptor 1 expression in human tooth pulp in relation to caries and pain.
        J Orofac Pain. 2005; 19: 248-260
        • Khan A.A.
        • Owatz C.B.
        • Schindler W.G.
        • et al.
        Measurement of mechanical allodynia and local anesthetic efficacy in patients with irreversible pulpitis and acute periradicular periodontitis.
        J Endod. 2007; 33: 796-799
        • Cavanaugh D.J.
        • Chesler A.T.
        • Braz J.M.
        • et al.
        Restriction of transient receptor potential vanilloid-1 to the peptidergic subset of primary afferent neurons follows its developmental downregulation in nonpeptidergic neurons.
        J Neurosci. 2011; 31: 10119-10127
        • Stander S.
        • Moormann C.
        • Schumacher M.
        • et al.
        Expression of vanilloid receptor subtype 1 in cutaneous sensory nerve fibers, mast cells, and epithelial cells of appendage structures.
        Exp Dermatol. 2004; 13: 129-139
        • Smeyne R.J.
        • Klein R.
        • Schnapp A.
        • et al.
        Severe sensory and sympathetic neuropathies in mice carrying a disrupted Trk/NGF receptor gene.
        Nature. 1994; 368: 246-249
        • Gingrich J.A.
        • Hen R.
        The broken mouse: the role of development, plasticity and environment in the interpretation of phenotypic changes in knockout mice.
        Curr Opin Neurobiol. 2000; 10: 146-152
        • Jancso G.
        • Obal Jr., F.
        • Toth-Kasa I.
        • et al.
        The modulation of cutaneous inflammatory reactions by peptide-containing sensory nerves.
        Int J Tissue React. 1985; 7: 449-457
        • Richardson J.D.
        • Vasko M.R.
        Cellular mechanisms of neurogenic inflammation.
        J Pharmacol Exp Ther. 2002; 302: 839-845
        • Mikami N.
        • Matsushita H.
        • Kato T.
        • et al.
        Calcitonin gene-related peptide is an important regulator of cutaneous immunity: effect on dendritic cell and T cell functions.
        J Immunol. 2011; 186: 6886-6893
        • Baliu-Pique M.
        • Jusek G.
        • Holzmann B.
        Neuroimmunological communication via CGRP promotes the development of a regulatory phenotype in TLR4-stimulated macrophages.
        Eur J Immunol. 2014; 44: 3708-3716
        • Owan I.
        • Ibaraki K.
        The role of calcitonin gene-related peptide (CGRP) in macrophages: the presence of functional receptors and effects on proliferation and differentiation into osteoclast-like cells.
        Bone Miner. 1994; 24: 151-164
        • Zaidi M.
        • Fuller K.
        • Bevis P.J.
        • et al.
        Calcitonin gene-related peptide inhibits osteoclastic bone resorption: a comparative study.
        Calcif Tissue Int. 1987; 40: 149-154