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
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2012

Open Access 01-12-2012 | Research

Chemokine CCL2 and its receptor CCR2 in the medullary dorsal horn are involved in trigeminal neuropathic pain

Authors: Zhi-Jun Zhang, Yu-Lin Dong, Ying Lu, Su Cao, Zhi-Qi Zhao, Yong-Jing Gao

Published in: Journal of Neuroinflammation | Issue 1/2012

Login to get access

Abstract

Background

Neuropathic pain in the trigeminal system is frequently observed in clinic, but the mechanisms involved are largely unknown. In addition, the function of immune cells and related chemicals in the mechanism of pain has been recognized, whereas few studies have addressed the potential role of chemokines in the trigeminal system in chronic pain. The present study was undertaken to test the hypothesis that chemokine C-C motif ligand 2 (CCL2)-chemokine C-C motif receptor 2 (CCR2) signaling in the trigeminal nucleus is involved in the maintenance of trigeminal neuropathic pain.

Methods

The inferior alveolar nerve and mental nerve transection (IAMNT) was used to induce trigeminal neuropathic pain. The expression of ATF3, CCL2, glial fibrillary acidic protein (GFAP), and CCR2 were detected by immunofluorescence histochemical staining and western blot. The cellular localization of CCL2 and CCR2 were examined by immunofluorescence double staining. The effect of a selective CCR2 antagonist, RS504393 on pain hypersensitivity was checked by behavioral testing.

Results

IAMNT induced persistent (>21 days) heat hyperalgesia of the orofacial region and ATF3 expression in the mandibular division of the trigeminal ganglion. Meanwhile, CCL2 expression was increased in the medullary dorsal horn (MDH) from 3 days to 21 days after IAMNT. The induced CCL2 was colocalized with astroglial marker GFAP, but not with neuronal marker NeuN or microglial marker OX-42. Astrocytes activation was also found in the MDH and it started at 3 days, peaked at 10 days and maintained at 21 days after IAMNT. In addition, CCR2 was upregulated by IAMNT in the ipsilateral medulla and lasted for more than 21 days. CCR2 was mainly colocalized with NeuN and few cells were colocalized with GFAP. Finally, intracisternal injection of CCR2 antagonist, RS504393 (1, 10 μg) significantly attenuated IAMNT-induced heat hyperalgesia.

Conclusion

The data suggest that CCL2-CCR2 signaling may be involved in the maintenance of orofacial neuropathic pain via astroglial–neuronal interaction. Targeting CCL2-CCR2 signaling may be a potentially important new treatment strategy for trigeminal neuralgia.
Literature
1.
Watkins LR, Maier SF: Glia: a novel drug discovery target for clinical pain. Nat Rev Drug Discov 2003, 2:973–985.CrossRefPubMed
2.
Romero-Sandoval EA, Horvath RJ, DeLeo JA: Neuroimmune interactions and pain: focus on glial-modulating targets. Curr Opin Investig Drugs 2008, 9:726–734.PubMedPubMedCentral
3.
Tsuda M, Inoue K, Salter MW: Neuropathic pain and spinal microglia: a big problem from molecules in “small” glia. Trends Neurosci 2005, 28:101–107.CrossRefPubMed
4.
Marchand F, Perretti M, McMahon SB: Role of the immune system in chronic pain. Nat Rev Neurosci 2005, 6:521–532.CrossRefPubMed
5.
Sessle BJ: Glia: non-neural players in orofacial pain. J Orofac Pain 2007, 21:169–170.PubMed
6.
Garrison CJ, Dougherty PM, Carlton SM: GFAP expression in lumbar spinal cord of naive and neuropathic rats treated with MK-801. Exp Neurol 1994, 129:237–243.CrossRefPubMed
7.
Colburn RW, Rickman AJ, DeLeo JA: The effect of site and type of nerve injury on spinal glial activation and neuropathic pain behavior. Exp Neurol 1999, 157:289–304.CrossRefPubMed
8.
Zhuang ZY, Wen YR, Zhang DR, Borsello T, Bonny C, Strichartz GR, Decosterd I, Ji RR: A peptide c-Jun N-terminal kinase (JNK) inhibitor blocks mechanical allodynia after spinal nerve ligation: respective roles of JNK activation in primary sensory neurons and spinal astrocytes for neuropathic pain development and maintenance. J Neurosci 2006, 26:3551–3560.CrossRefPubMed
9.
Piao ZG, Cho IH, Park CK, Hong JP, Choi SY, Lee SJ, Lee S, Park K, Kim JS, Oh SB: Activation of glia and microglial p38 MAPK in medullary dorsal horn contributes to tactile hypersensitivity following trigeminal sensory nerve injury. Pain 2006, 121:219–231.CrossRefPubMed
10.
Xu M, Aita M, Chavkin C: Partial infraorbital nerve ligation as a model of trigeminal nerve injury in the mouse: behavioral, neural, and glial reactions. J Pain 2008, 9:1036–1048.CrossRefPubMedPubMedCentral
11.
Lee S, Zhao YQ, Ribeiro-da-Silva A, Zhang J: Distinctive response of CNS glial cells in oro-facial pain associated with injury, infection and inflammation. Mol Pain 2010, 6:79.CrossRefPubMedPubMedCentral
12.
Watkins LR, Maier SF: Beyond neurons: evidence that immune and glial cells contribute to pathological pain states. Physiol Rev 2002, 82:981–1011.CrossRefPubMed
13.
14.
Inoue K: The function of microglia through purinergic receptors: neuropathic pain and cytokine release. Pharmacol Ther 2006, 109:210–226.CrossRefPubMed
15.
16.
Abbadie C, Bhangoo S, De Koninck Y, Malcangio M, Melik-Parsadaniantz S, White FA: Chemokines and pain mechanisms. Brain Res Rev 2009, 60:125–134.CrossRefPubMed
17.
Mennicken F, Maki R, de Souza EB, Quirion R: Chemokines and chemokine receptors in the CNS: a possible role in neuroinflammation and patterning. Trends Pharmacol Sci 1999, 20:73–78.CrossRefPubMed
18.
Scholz J, Woolf CJ: The neuropathic pain triad: neurons, immune cells and glia. Nat Neurosci 2007, 10:1361–1368.CrossRefPubMed
19.
20.
Miller RJ, Rostene W, Apartis E, Banisadr G, Biber K, Milligan ED, White FA, Zhang J: Chemokine action in the nervous system. J Neurosci 2008, 28:11792–11795.CrossRefPubMedPubMedCentral
21.
Ransohoff RM, Liu L, Cardona AE: Chemokines and chemokine receptors: multipurpose players in neuroinflammation. Int Rev Neurobiol 2007, 82:187–204.CrossRefPubMed
22.
Wain JH, Kirby JA, Ali S: Leucocyte chemotaxis: Examination of mitogen-activated protein kinase and phosphoinositide 3-kinase activation by Monocyte Chemoattractant Proteins-1, -2, -3 and −4. Clin Exp Immunol 2002, 127:436–444.CrossRefPubMedPubMedCentral
23.
Ji RR, Gereau RWt, Malcangio M, Strichartz GR: MAP kinase and pain. Brain Res Rev 2009, 60:135–148.CrossRefPubMed
24.
Abbadie C, Lindia JA, Cumiskey AM, Peterson LB, Mudgett JS, Bayne EK, DeMartino JA, MacIntyre DE, Forrest MJ: Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2. Proc Natl Acad Sci U S A 2003, 100:7947–7952.CrossRefPubMedPubMedCentral
25.
Zhang J, Shi XQ, Echeverry S, Mogil JS, De Koninck Y, Rivest S: Expression of CCR2 in both resident and bone marrow-derived microglia plays a critical role in neuropathic pain. J Neurosci 2007, 27:12396–12406.CrossRefPubMed
26.
Menetski J, Mistry S, Lu M, Mudgett JS, Ransohoff RM, Demartino JA, Macintyre DE, Abbadie C: Mice overexpressing chemokine ligand 2 (CCL2) in astrocytes display enhanced nociceptive responses. Neuroscience 2007, 149:706–714.CrossRefPubMed
27.
Jung H, Toth PT, White FA, Miller RJ: Monocyte chemoattractant protein-1 functions as a neuromodulator in dorsal root ganglia neurons. J Neurochem 2008, 104:254–263.PubMed
28.
Tanaka T, Minami M, Nakagawa T, Satoh M: Enhanced production of monocyte chemoattractant protein-1 in the dorsal root ganglia in a rat model of neuropathic pain: possible involvement in the development of neuropathic pain. Neurosci Res 2004, 48:463–469.CrossRefPubMed
29.
Thacker MA, Clark AK, Bishop T, Grist J, Yip PK, Moon LD, Thompson SW, Marchand F, McMahon SB: CCL2 is a key mediator of microglia activation in neuropathic pain states. Eur J Pain 2009, 13:263–272.CrossRefPubMed
30.
Zhang J, De Koninck Y: Spatial and temporal relationship between monocyte chemoattractant protein-1 expression and spinal glial activation following peripheral nerve injury. J Neurochem 2006, 97:772–783.CrossRefPubMed
31.
Jeon SM, Lee KM, Park ES, Jeon YH, Cho HJ: Monocyte chemoattractant protein-1 immunoreactivity in sensory ganglia and hindpaw after adjuvant injection. Neuroreport 2008, 19:183–186.CrossRefPubMed
32.
33.
Old EA, Malcangio M: Chemokine mediated neuron-glia communication and aberrant signalling in neuropathic pain states. Curr Opin Pharmacol 2012, 12:67–73.CrossRefPubMed
34.
Sessle BJ: Acute and chronic craniofacial pain: brainstem mechanisms of nociceptive transmission and neuroplasticity, and their clinical correlates. Crit Rev Oral Biol Med 2000, 11:57–91.CrossRefPubMed
35.
Dubner R, Bennett GJ: Spinal and trigeminal mechanisms of nociception. Annu Rev Neurosci 1983, 6:381–418.CrossRefPubMed
36.
Okada-Ogawa A, Suzuki I, Sessle BJ, Chiang CY, Salter MW, Dostrovsky JO, Tsuboi Y, Kondo M, Kitagawa J, Kobayashi A, et al.: Astroglia in medullary dorsal horn (trigeminal spinal subnucleus caudalis) are involved in trigeminal neuropathic pain mechanisms. J Neurosci 2009, 29:11161–11171.CrossRefPubMedPubMedCentral
37.
Terayama R, Fujisawa N, Yamaguchi D, Omura S, Ichikawa H, Sugimoto T: Differential activation of mitogen-activated protein kinases and glial cells in the trigeminal sensory nuclear complex following lingual nerve injury. Neurosci Res 2011, 69:100–110.CrossRefPubMed
38.
Nakagawa K, Takeda M, Tsuboi Y, Kondo M, Kitagawa J, Matsumoto S, Kobayashi A, Sessle BJ, Shinoda M, Iwata K: Alteration of primary afferent activity following inferior alveolar nerve transection in rats. Mol Pain 2010, 6:9.CrossRefPubMedPubMedCentral
39.
Saito K, Hitomi S, Suzuki I, Masuda Y, Kitagawa J, Tsuboi Y, Kondo M, Sessle BJ, Iwata K: Modulation of trigeminal spinal subnucleus caudalis neuronal activity following regeneration of transected inferior alveolar nerve in rats. J Neurophysiol 2008, 99:2251–2263.CrossRefPubMed
40.
Tsuboi Y, Takeda M, Tanimoto T, Ikeda M, Matsumoto S, Kitagawa J, Teramoto K, Simizu K, Yamazaki Y, Shima A, et al.: Alteration of the second branch of the trigeminal nerve activity following inferior alveolar nerve transection in rats. Pain 2004, 111:323–334.CrossRefPubMed
41.
Zimmermann M: Ethical guidelines for investigations of experimental pain in conscious animals. Pain 1983, 16:109–110.CrossRefPubMed
42.
Tsujino H, Kondo E, Fukuoka T, Dai Y, Tokunaga A, Miki K, Yonenobu K, Ochi T, Noguchi K: Activating transcription factor 3 (ATF3) induction by axotomy in sensory and motoneurons: A novel neuronal marker of nerve injury. Mol Cell Neurosci 2000, 15:170–182.CrossRefPubMed
43.
Jung H, Bhangoo S, Banisadr G, Freitag C, Ren D, White FA, Miller RJ: Visualization of chemokine receptor activation in transgenic mice reveals peripheral activation of CCR2 receptors in states of neuropathic pain. J Neurosci 2009, 29:8051–8062.CrossRefPubMedPubMedCentral
44.
Kurihara T, Bravo R: Cloning and functional expression of mCCR2, a murine receptor for the C-C chemokines JE and FIC. J Biol Chem 1996, 271:11603–11607.CrossRefPubMed
45.
Tsuzuki K, Fukuoka T, Sakagami M, Noguchi K: Increase of preprotachykinin mRNA in the uninjured mandibular neurons after rat infraorbital nerve transection. Neurosci Lett 2003, 345:57–60.CrossRefPubMed
46.
White FA, Sun J, Waters SM, Ma C, Ren D, Ripsch M, Steflik J, Cortright DN, Lamotte RH, Miller RJ: Excitatory monocyte chemoattractant protein-1 signaling is up-regulated in sensory neurons after chronic compression of the dorsal root ganglion. Proc Natl Acad Sci U S A 2005, 102:14092–14097.CrossRefPubMedPubMedCentral
47.
Gao YJ, Zhang L, Samad OA, Suter MR, Yasuhiko K, Xu ZZ, Park JY, Lind AL, Ma Q, Ji RR: JNK-induced MCP-1 production in spinal cord astrocytes contributes to central sensitization and neuropathic pain. J Neurosci 2009, 29:4096–4108.CrossRefPubMedPubMedCentral
48.
Knerlich-Lukoschus F, Juraschek M, Blomer U, Lucius R, Mehdorn HM, Held-Feindt J: Force-dependent development of neuropathic central pain and time-related CCL2/CCR2 expression after graded spinal cord contusion injuries of the rat. J Neurotrauma 2008, 25:427–448.CrossRefPubMed
49.
Berman JW, Guida MP, Warren J, Amat J, Brosnan CF: Localization of monocyte chemoattractant peptide-1 expression in the central nervous system in experimental autoimmune encephalomyelitis and trauma in the rat. J Immunol 1996, 156:3017–3023.PubMed
50.
McManus C, Berman JW, Brett FM, Staunton H, Farrell M, Brosnan CF: MCP-1, MCP-2 and MCP-3 expression in multiple sclerosis lesions: an immunohistochemical and in situ hybridization study. J Neuroimmunol 1998, 86:20–29.CrossRefPubMed
51.
Van Der Voorn P, Tekstra J, Beelen RH, Tensen CP, Van Der Valk P, De Groot CJ: Expression of MCP-1 by reactive astrocytes in demyelinating multiple sclerosis lesions. Am J Pathol 1999, 154:45–51.CrossRefPubMedPubMedCentral
52.
Che X, Ye W, Panga L, Wu DC, Yang GY: Monocyte chemoattractant protein-1 expressed in neurons and astrocytes during focal ischemia in mice. Brain Res 2001, 902:171–177.CrossRefPubMed
53.
Kim JS, Gautam SC, Chopp M, Zaloga C, Jones ML, Ward PA, Welch KM: Expression of monocyte chemoattractant protein-1 and macrophage inflammatory protein-1 after focal cerebral ischemia in the rat. J Neuroimmunol 1995, 56:127–134.CrossRefPubMed
54.
Glabinski AR, Balasingam V, Tani M, Kunkel SL, Strieter RM, Yong VW, Ransohoff RM: Chemokine monocyte chemoattractant protein-1 is expressed by astrocytes after mechanical injury to the brain. J Immunol 1996, 156:4363–4368.PubMed
55.
Johnstone M, Gearing AJ, Miller KM: A central role for astrocytes in the inflammatory response to beta-amyloid; chemokines, cytokines and reactive oxygen species are produced. J Neuroimmunol 1999, 93:182–193.CrossRefPubMed
56.
Croitoru-Lamoury J, Guillemin GJ, Boussin FD, Mognetti B, Gigout LI, Cheret A, Vaslin B, Le Grand R, Brew BJ, Dormont D: Expression of chemokines and their receptors in human and simian astrocytes: evidence for a central role of TNF alpha and IFN gamma in CXCR4 and CCR5 modulation. Glia 2003, 41:354–370.CrossRefPubMed
57.
Meeuwsen S, Persoon-Deen C, Bsibsi M, Ravid R, van Noort JM: Cytokine, chemokine and growth factor gene profiling of cultured human astrocytes after exposure to proinflammatory stimuli. Glia 2003, 43:243–253.CrossRefPubMed
58.
Mojsilovic-Petrovic J, Callaghan D, Cui H, Dean C, Stanimirovic DB, Zhang W: Hypoxia-inducible factor-1 (HIF-1) is involved in the regulation of hypoxia-stimulated expression of monocyte chemoattractant protein-1 (MCP-1/CCL2) and MCP-5 (Ccl12) in astrocytes. J Neuroinflammation 2007, 4:12.CrossRefPubMedPubMedCentral
59.
60.
61.
62.
Guo W, Wang H, Watanabe M, Shimizu K, Zou S, LaGraize SC, Wei F, Dubner R, Ren K: Glial-cytokine-neuronal interactions underlying the mechanisms of persistent pain. J Neurosci 2007, 27:6006–6018.CrossRefPubMedPubMedCentral
63.
Hidaka K, Ono K, Harano N, Sago T, Nunomaki M, Shiiba S, Nakanishi O, Fukushima H, Inenaga K: Central glial activation mediates cancer-induced pain in a rat facial cancer model. Neuroscience 2011, 180:334–343.CrossRefPubMed
64.
Parpura V, Zorec R: Gliotransmission: Exocytotic release from astrocytes. Brain Res Rev 2010, 63:83–92.CrossRefPubMed
65.
Chiang CY, Dostrovsky JO, Iwata K, Sessle BJ: Role of glia in orofacial pain. Neuroscientist 2011, 17:303–320.CrossRefPubMed
66.
Zhang RX, Liu B, Li A, Wang L, Ren K, Qiao JT, Berman BM, Lao L: Interleukin 1beta facilitates bone cancer pain in rats by enhancing NMDA receptor NR-1 subunit phosphorylation. Neuroscience 2008, 154:1533–1538.CrossRefPubMedPubMedCentral
67.
Wei F, Guo W, Zou S, Ren K, Dubner R: Supraspinal glial-neuronal interactions contribute to descending pain facilitation. J Neurosci 2008, 28:10482–10495.CrossRefPubMedPubMedCentral
68.
Zhang RX, Li A, Liu B, Wang L, Ren K, Zhang H, Berman BM, Lao L: IL-1ra alleviates inflammatory hyperalgesia through preventing phosphorylation of NMDA receptor NR-1 subunit in rats. Pain 2008, 135:232–239.CrossRefPubMed
69.
Kawasaki Y, Zhang L, Cheng JK, Ji RR: Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in regulating synaptic and neuronal activity in the superficial spinal cord. J Neurosci 2008, 28:5189–5194.CrossRefPubMedPubMedCentral
70.
Saederup N, Cardona AE, Croft K, Mizutani M, Cotleur AC, Tsou CL, Ransohoff RM, Charo IF: Selective chemokine receptor usage by central nervous system myeloid cells in CCR2-red fluorescent protein knock-in mice. PLoS One 2010, 5:e13693.CrossRefPubMedPubMedCentral
71.
Van Steenwinckel J, Reaux-Le Goazigo A, Pommier B, Mauborgne A, Dansereau MA, Kitabgi P, Sarret P, Pohl M, Melik Parsadaniantz S: CCL2 released from neuronal synaptic vesicles in the spinal cord is a major mediator of local inflammation and pain after peripheral nerve injury. J Neurosci 2011, 31:5865–5875.CrossRefPubMed
72.
Gosselin RD, Varela C, Banisadr G, Mechighel P, Rostene W, Kitabgi P, Melik-Parsadaniantz S: Constitutive expression of CCR2 chemokine receptor and inhibition by MCP-1/CCL2 of GABA-induced currents in spinal cord neurones. J Neurochem 2005, 95:1023–1034.CrossRefPubMed
73.
Foresti ML, Arisi GM, Katki K, Montanez A, Sanchez RM, Shapiro LA: Chemokine CCL2 and its receptor CCR2 are increased in the hippocampus following pilocarpine-induced status epilepticus. J Neuroinflammation 2009, 6:40.CrossRefPubMedPubMedCentral
74.
Bhangoo S, Ren D, Miller RJ, Henry KJ, Lineswala J, Hamdouchi C, Li B, Monahan PE, Chan DM, Ripsch MS, White FA: Delayed functional expression of neuronal chemokine receptors following focal nerve demyelination in the rat: a mechanism for the development of chronic sensitization of peripheral nociceptors. Mol Pain 2007, 3:38.CrossRefPubMedPubMedCentral
75.
Dansereau MA, Gosselin RD, Pohl M, Pommier B, Mechighel P, Mauborgne A, Rostene W, Kitabgi P, Beaudet N, Sarret P, Melik-Parsadaniantz S: Spinal CCL2 pronociceptive action is no longer effective in CCR2 receptor antagonist-treated rats. J Neurochem 2008, 106:757–769.CrossRefPubMed
76.
Serrano A, Pare M, McIntosh F, Elmes SJ, Martino G, Jomphe C, Lessard E, Lembo PM, Vaillancourt F, Perkins MN, Cao CQ: Blocking spinal CCR2 with AZ889 reversed hyperalgesia in a model of neuropathic pain. Mol Pain 2010, 6:90.CrossRefPubMedPubMedCentral
Metadata
Title
Chemokine CCL2 and its receptor CCR2 in the medullary dorsal horn are involved in trigeminal neuropathic pain
Authors
Zhi-Jun Zhang
Yu-Lin Dong
Ying Lu
Su Cao
Zhi-Qi Zhao
Yong-Jing Gao
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2012
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/1742-2094-9-136

Other articles of this Issue 1/2012

Journal of Neuroinflammation 1/2012 Go to the issue

Research

Evaluating the role of IL-11, a novel cytokine in the IL-6 family, in a mouse model of spinal cord injury

Review

Who fans the flames of Alzheimer's disease brains? Misfolded tau on the crossroad of neurodegenerative and inflammatory pathways

Research

Disrupted sleep without sleep curtailment induces sleepiness and cognitive dysfunction via the tumor necrosis factor-α pathway

Research

Transforming growth factor β1-induced astrocyte migration is mediated in part by activating 5-lipoxygenase and cysteinyl leukotriene receptor 1

Short report

Increased blood-cerebrospinal fluid transfer of albumin in advanced Parkinson’s disease

Short report

TLR-4 ligation of dendritic cells is sufficient to drive pathogenic T cell function in experimental autoimmune encephalomyelitis