Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2017

Open Access 01-12-2017 | Research

Macrophages in trigeminal ganglion contribute to ectopic mechanical hypersensitivity following inferior alveolar nerve injury in rats

Authors: Dulguun Batbold, Masamichi Shinoda, Kuniya Honda, Akihiko Furukawa, Momoko Koizumi, Ryuta Akasaka, Satoshi Yamaguchi, Koichi Iwata

Published in: Journal of Neuroinflammation | Issue 1/2017

Login to get access

Abstract

Background

Accidental mandibular nerve injury may occur during tooth extraction or implant procedures, causing ectopic orofacial pain. The exact mechanisms underlying ectopic orofacial pain following mandibular nerve injury is still unknown. Here, we investigated the role of macrophages and tumor necrosis factor alpha (TNFα) in the trigeminal ganglion (TG) in ectopic orofacial pain following inferior alveolar nerve transection (IANX).

Methods

IANX was performed and the mechanical head-withdrawal threshold (MHWT) in the whisker pad skin ipsilateral to IANX was measured for 15 days. Expression of Iba1 in the TG was examined on day 3 after IANX, and the MHWT in the whisker pad skin ipsilateral to IANX was measured following successive intra-ganglion administration of the macrophage depletion agent liposomal clodronate Clophosome-A (LCCA). TNFα expression in the TG and the MHWT in the whisker pad skin ipsilateral to IANX following successive intra-ganglion administration of the TNFα blocker etanercept were measured on day 3 after IANX, and tumor necrosis factor receptor-1 (TNFR1) immunoreactive (IR) cells in the TG were analyzed immunohistochemically on day 3.

Results

The MHWT in the whisker pad skin was significantly decreased for 15 days, and the number of Iba1-IR cells was significantly increased in the TG on day 3 after IANX. Successive intra-ganglion administration of the macrophage depletion agent LCCA significantly reduced the increased number of Iba1-IR cells in the TG and reversed the IANX-induced decrease in MHWT in the whisker pad skin. TNFα expression was increased in the TG on day 3 after IANX and was reduced following successive intra-ganglion administration of the TNFα inhibitor etanercept. The decreased MHWT was also recovered by etanercept administration, and TNFR1-IR cells in the TG were increased on day 3 following IANX.

Conclusions

These findings suggest that signaling cascades resulting from the production of TNFα by infiltrated macrophages in the TG contributes to the development of ectopic mechanical allodynia in whisker pad skin following IANX.
Literature
1.
Renton T, Yilmaz Z, Gaballah K. Evaluation of trigeminal nerve injuries in relation to third molar surgery in a prospective patient cohort. Recommendations for prevention. Int J Oral Maxillofac Surg. 2012;41:1509–18.CrossRefPubMed
2.
Khawaja N, Renton T. Case studies on implant removal influencing the resolution of inferior alveolar nerve injury. Br Dent J. 2009;206:365–70.CrossRefPubMed
3.
Lin CS, SY W, Huang HY, et al. Systematic review and meta-analysis on incidence of altered sensation of mandibular implant surgery. PLoS One. 2016;11:e0154082.CrossRefPubMedPubMedCentral
4.
5.
Sugiyama T, Shinoda M, Watase T, et al. Nitric oxide signaling contributes to ectopic orofacial neuropathic pain. J Dent Res. 2013;92:1113–7.CrossRefPubMed
6.
7.
Kwon MJ, Kim J, Shin H, et al. Contribution of macrophages to enhanced regenerative capacity of dorsal root ganglia sensory neurons by conditioning injury. J Neurosci. 2013;33:15095–108.CrossRefPubMed
8.
Kwon MJ, Shin HY, Cui Y, et al. CCL2 mediates neuron-macrophage interactions to drive proregenerative macrophage activation following preconditioning injury. J Neurosci. 2015;35:15934–47.CrossRefPubMed
9.
Liu T, van Rooijen N, Tracey DJ. Depletion of macrophages reduces axonal degeneration and hyperalgesia following nerve injury. Pain. 2000;86:25–32.CrossRefPubMed
10.
Kobayashi Y, Kiguchi N, Fukazawa Y, et al. Macrophage-T cell interactions mediate neuropathic pain through the glucocorticoid-induced tumor necrosis factor ligand system. J Biol Chem. 2015;290:12603–13.CrossRefPubMedPubMedCentral
11.
Zhang H, Li Y, de Carvalho-Barbosa M, et al. Dorsal root ganglion infiltration by macrophages contributes to paclitaxel chemotherapy-induced peripheral neuropathy. J Pain. 2016;17:775–86.CrossRefPubMedPubMedCentral
12.
George A, Marziniak M, Schafers M, et al. Thalidomide treatment in chronic constrictive neuropathy decreases endoneurial tumor necrosis factor-alpha, increases interleukin-10 and has long-term effects on spinal cord dorsal horn met-enkephalin. Pain. 2000;88:267–75.CrossRefPubMed
13.
Pang M, Yuan Y, Wang D, et al. Recombinant CC16 protein inhibits the production of pro-inflammatory cytokines via NF-kappaB and p38 MAPK pathways in LPS-activated RAW264.7 macrophages. Acta Biochim Biophys Sin Shanghai. 2017;49:435–43.CrossRefPubMedPubMedCentral
14.
Zimmermann M. Ethical guidelines for investigations of experimental pain in conscious animals. Pain. 1983;16:109–10.CrossRefPubMed
15.
Iwata K, Imai T, Tsuboi Y, et al. Alteration of medullary dorsal horn neuronal activity following inferior alveolar nerve transection in rats. J Neurophysiol. 2001;86:2868–77.PubMed
16.
Katagiri A, Shinoda M, Honda K, et al. Satellite glial cell P2Y12 receptor in the trigeminal ganglion is involved in lingual neuropathic pain mechanisms in rats. Mol Pain. 2012;8:23.CrossRefPubMedPubMedCentral
17.
Van Rooijen N, Sanders A. Liposome mediated depletion of macrophages: mechanism of action, preparation of liposomes and applications. J Immunol Methods. 1994;174:83–93.CrossRefPubMed
18.
Okada-Ogawa A, Nakaya Y, Imamura Y, et al. Involvement of medullary GABAergic system in extraterritorial neuropathic pain mechanisms associated with inferior alveolar nerve transection. Exp Neurol. 2015;267:42–52.CrossRefPubMed
19.
Ohsawa K, Imai Y, Kanazawa H, et al. Involvement of Iba1 in membrane ruffling and phagocytosis of macrophages/microglia. J Cell Sci. 2000;113(Pt 17):3073–84.PubMed
20.
Harvey LD, Yin Y, Attarwala IY, et al. Administration of DHA reduces endoplasmic reticulum stress-associated inflammation and alters microglial or macrophage activation in traumatic brain injury. ASN Neuro. 2015;7(6): doi:10.​1177/​1759091415618969​.
21.
Donegan M, Kernisant M, Cua C, et al. Satellite glial cell proliferation in the trigeminal ganglia after chronic constriction injury of the infraorbital nerve. Glia. 2013;61:2000–8.CrossRefPubMedPubMedCentral
22.
Komori T, Morikawa Y, Inada T, et al. Site-specific subtypes of macrophages recruited after peripheral nerve injury. Neuroreport. 2011;22:911–7.CrossRefPubMed
23.
Lu X, Richardson PM. Responses of macrophages in rat dorsal root ganglia following peripheral nerve injury. J Neurocytol. 1993;22:334–41.CrossRefPubMed
24.
Abbadie C, Lindia JA, Cumiskey AM, et al. Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2. Proc Natl Acad Sci U S A. 2003;100:7947–52.CrossRefPubMedPubMedCentral
25.
Kim D, You B, Lim H, et al. Toll-like receptor 2 contributes to chemokine gene expression and macrophage infiltration in the dorsal root ganglia after peripheral nerve injury. Mol Pain. 2011;7:74.PubMedPubMedCentral
26.
Mass E, Ballesteros I, Farlik M, et al. Specification of tissue-resident macrophages during organogenesis. Science. 2016;353(6304):aaf4238.
27.
Hashimoto D, Chow A, Noizat C, et al. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity. 2013;38:792–804.CrossRefPubMed
28.
Raghavendra V, Tanga F, Rutkowski MD, et al. Anti-hyperalgesic and morphine-sparing actions of propentofylline following peripheral nerve injury in rats: mechanistic implications of spinal glia and proinflammatory cytokines. Pain. 2003;104:655–64.CrossRefPubMed
29.
Wagner R, Myers RR. Endoneurial injection of TNF-alpha produces neuropathic pain behaviors. Neuroreport. 1996;7:2897–901.CrossRefPubMed
30.
Wang CL, CY L, Pi CC, et al. Extracellular polysaccharides produced by Ganoderma formosanum stimulate macrophage activation via multiple pattern-recognition receptors. BMC Complement Altern Med. 2012;12:119.CrossRefPubMedPubMedCentral
31.
Fu C, Yin Z, Yu D, et al. Substance P and calcitonin gene-related peptide expression in dorsal root ganglia in sciatic nerve injury rats. Neural Regen Res. 2013;8:3124–30.PubMedPubMedCentral
32.
Sun J, Ramnath RD, Zhi L, et al. Substance P enhances NF-kappaB transactivation and chemokine response in murine macrophages via ERK1/2 and p38 MAPK signaling pathways. Am J Physiol Cell Physiol. 2008;294:C1586–96.CrossRefPubMed
33.
Matsumoto K, Nakajima T, Sakai H, et al. Increased expression of 5-HT3 and NK 1 receptors in 5-fluorouracil-induced mucositis in mouse jejunum. Dig Dis Sci. 2013;58:3440–51.CrossRefPubMed
34.
Bardelli C, Gunella G, Varsaldi F, et al. Expression of functional NK1 receptors in human alveolar macrophages: superoxide anion production, cytokine release and involvement of NF-kappaB pathway. Br J Pharmacol. 2005;145:385–96.CrossRefPubMedPubMedCentral
35.
Nomura H, Furuta A, Tanaka Y, et al. Forced retraction of spinal root injury enhances activation of p38 MAPK cascade in infiltrating macrophages. Neuropathology. 2005;25:37–47.CrossRefPubMed
36.
Chen X, Pang RP, Shen KF, et al. TNF-alpha enhances the currents of voltage gated sodium channels in uninjured dorsal root ganglion neurons following motor nerve injury. Exp Neurol. 2011;227:279–86.CrossRefPubMed
37.
Miao P, Madec K, Gong Y, et al. Axotomy-induced up-regulation of tumor necrosis factor-alpha in the dorsal root ganglia. Neurol Res. 2008;30:623–31.CrossRefPubMed
38.
Schafers M, Lee DH, Brors D, et al. Increased sensitivity of injured and adjacent uninjured rat primary sensory neurons to exogenous tumor necrosis factor-alpha after spinal nerve ligation. J Neurosci. 2003;23:3028–38.PubMed
39.
He XH, Zang Y, Chen X, et al. TNF-alpha contributes to up-regulation of Nav1.3 and Nav1.8 in DRG neurons following motor fiber injury. Pain. 2010;151:266–79.CrossRefPubMed
40.
Jin X, Gereau RW. Acute p38-mediated modulation of tetrodotoxin-resistant sodium channels in mouse sensory neurons by tumor necrosis factor-alpha. J Neurosci. 2006;26:246–55.CrossRefPubMed
41.
Czeschik JC, Hagenacker T, Schafers M, et al. TNF-alpha differentially modulates ion channels of nociceptive neurons. Neurosci Lett. 2008;434:293–8.CrossRefPubMed
42.
Leo M, Argalski S, Schafers M, et al. Modulation of voltage-gated sodium channels by activation of tumor necrosis factor receptor-1 and receptor-2 in small DRG neurons of rats. Mediat Inflamm. 2015;2015:124942.CrossRef
43.
Kanno T, Yaguchi T, Nishizaki T. Noradrenaline stimulates ATP release from DRG neurons by targeting beta(3) adrenoceptors as a factor of neuropathic pain. J Cell Physiol. 2010;224:345–51.CrossRefPubMed
44.
Zhang X, Chen Y, Wang C, et al. Neuronal somatic ATP release triggers neuron-satellite glial cell communication in dorsal root ganglia. Proc Natl Acad Sci U S A. 2007;104:9864–9.CrossRefPubMedPubMedCentral
45.
Dubovy P, Jancalek R, Klusakova I, et al. Intra- and extraneuronal changes of immunofluorescence staining for TNF-alpha and TNFR1 in the dorsal root ganglia of rat peripheral neuropathic pain models. Cell Mol Neurobiol. 2006;26:1205–17.CrossRefPubMed
46.
Hatashita S, Sekiguchi M, Kobayashi H, et al. Contralateral neuropathic pain and neuropathology in dorsal root ganglion and spinal cord following hemilateral nerve injury in rats. Spine (Phila Pa 1976). 2008;33:1344–51.CrossRef
47.
Sommer C, Schmidt C, George A. Hyperalgesia in experimental neuropathy is dependent on the TNF receptor 1. Exp Neurol. 1998;151:138–42.CrossRefPubMed
Metadata
Title
Macrophages in trigeminal ganglion contribute to ectopic mechanical hypersensitivity following inferior alveolar nerve injury in rats
Authors
Dulguun Batbold
Masamichi Shinoda
Kuniya Honda
Akihiko Furukawa
Momoko Koizumi
Ryuta Akasaka
Satoshi Yamaguchi
Koichi Iwata
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2017
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-017-1022-3

Other articles of this Issue 1/2017

Journal of Neuroinflammation 1/2017 Go to the issue

Research

Enhanced susceptibility of triple transgenic Alzheimer’s disease (3xTg-AD) mice to acute infection

Research

YKL-40 (Chitinase 3-like I) is expressed in a subset of astrocytes in Alzheimer’s disease and other tauopathies

Research

Proteomic analysis of aged microglia: shifts in transcription, bioenergetics, and nutrient response

Research

In vivo TSPO and cannabinoid receptor type 2 availability early in post-stroke neuroinflammation in rats: a positron emission tomography study

Research

Intrathecal Th17- and B cell-associated cytokine and chemokine responses in relation to clinical outcome in Lyme neuroborreliosis: a large retrospective study

Research

Alleviation of secondary brain injury, posttraumatic inflammation, and brain edema formation by inhibition of factor XIIa