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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2015

Open Access 01-12-2015 | Research

SDF1–CXCR4 signaling contributes to persistent pain and hypersensitivity via regulating excitability of primary nociceptive neurons: involvement of ERK-dependent Nav1.8 up-regulation

Authors: Fei Yang, Wei Sun, Yan Yang, Yan Wang, Chun-Li Li, Han Fu, Xiao-Liang Wang, Fan Yang, Ting He, Jun Chen

Published in: Journal of Neuroinflammation | Issue 1/2015

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Abstract

Background

Pain is one critical hallmark of inflammatory responses. A large number of studies have demonstrated that stromal cell-derived factor 1 (SDF1, also named as CXCL12) and its cognate receptor C-X-C chemokine receptor type 4 (CXCR4) play an important role in immune reaction and inflammatory processes. However, whether and how SDF1–CXCR4 signaling is involved in inflammatory pain remains unclear.

Methods

Under the intraplantar (i.pl.) bee venom (BV) injection-induced persistent inflammatory pain state, the changes of SDF1 and CXCR4 expression and cellular localization in the rat dorsal root ganglion (DRG) were detected by immunofluorescent staining. The role of SDF1 and CXCR4 in the hyperexcitability of primary nociceptor neurons was assessed by electrophysiological recording. Western blot analysis was used to quantify the DRG Nav1.8 and phosphorylation of ERK (pERK) expression. Behavioral tests were conducted to evaluate the roles of CXCR4 as well as extracellular signal-regulated kinase (ERK) and Nav1.8 in the BV-induced persistent pain and hypersensitivity.

Results

We showed that both SDF1 and CXCR4 were dramatically up-regulated in the DRG in i.pl. BV-induced inflammatory pain model. Double immunofluorescent staining showed that CXCR4 was localized in all sizes (large, medium, and small) of DRG neuronal soma, while SDF1 was exclusively expressed in satellite glial cells (SGCs). Electrophysiological recording showed that bath application with AMD3100, a potent and selective CXCR4 inhibitor, could reverse the hyperexcitability of medium- and small-sized DRG neurons harvested from rats following i.pl. BV injection. Furthermore, we demonstrated that the BV-induced ERK activation and Nav1.8 up-regulation in the DRG could be blocked by pre-antagonism against CXCR4 in the periphery with AMD3100 as well as by blockade of ERK activation by intrathecal (i.t.) or intraplantar (i.pl.) U0126. At behavioral level, the BV-induced persistent spontaneous pain as well as primary mechanical and thermal hypersensitivity could also be significantly suppressed by blocking CXCR4 and Nav1.8 in the periphery as well as by inhibition of ERK activation at the DRG level.

Conclusions

The present results suggest that peripheral inflammatory pain state can trigger over release of SDF1 from the activated SGCs in the DRG by which SGC-neuronal cross-talk is mediated by SDF1–CXCR4 coupling that result in subsequent ERK-dependent Nav1.8 up-regulation, leading to hyperexcitability of tonic type of the primary nociceptor cells and development and maintenance of persistent spontaneous pain and hypersensitivity.
Literature
1.
Ma W, Quirion R. Inflammatory mediators modulating the transient receptor potential vanilloid 1 receptor: therapeutic targets to treat inflammatory and neuropathic pain. Expert Opin Ther Targets. 2007;11:307–20.CrossRefPubMed
2.
Gosselin RD, Dansereau MA, Pohl M, Kitabgi P, Beaudet N, Sarret P, et al. Chemokine network in the nervous system: a new target for pain relief. Curr Med Chem. 2008;15:2866–75.CrossRefPubMed
3.
Cao DL, Zhang ZJ, Xie RG, Jiang BC, Ji RR, Gao YJ. Chemokine CXCL1 enhances inflammatory pain and increases NMDA receptor activity and COX-2 expression in spinal cord neurons via activation of CXCR2. Exp Neurol. 2014;261:328–36.CrossRefPubMed
4.
5.
Turner MD, Nedjai B, Hurst T, Pennington DJ. Cytokines and chemokines: at the crossroads of cell signalling and inflammatory disease. Biochim Biophys Acta. 1843;2014:2563–82.
6.
Miller RJ, Jung H, Bhangoo SK, White FA. Cytokine and chemokine regulation of sensory neuron function. Handb Exp Pharmacol. 2009;194:417–49.CrossRefPubMed
7.
8.
Reaux-Le GA, Van Steenwinckel J, Rostene W, Melik PS. Current status of chemokines in the adult CNS. Prog Neurobiol. 2013;104:67–92.CrossRef
9.
Reaux-Le GA, Rivat C, Kitabgi P, Pohl M, Melik PS. Cellular and subcellular localization of CXCL12 and CXCR4 in rat nociceptive structures: physiological relevance. Eur J Neurosci. 2012;36:2619–31.CrossRef
10.
Klein RS, Rubin JB, Gibson HD, DeHaan EN, Alvarez-Hernandez X, Segal RA, et al. SDF-1 alpha induces chemotaxis and enhances Sonic hedgehog-induced proliferation of cerebellar granule cells. Development. 2001;128:1971–81.PubMed
11.
Wang Y, Deng Y, Zhou GQ. SDF-1alpha/CXCR4-mediated migration of systemically transplanted bone marrow stromal cells towards ischemic brain lesion in a rat model. Brain Res. 2008;1195:104–12.CrossRefPubMed
12.
Banisadr G, Frederick TJ, Freitag C, Ren D, Jung H, Miller SD, et al. The role of CXCR4 signaling in the migration of transplanted oligodendrocyte progenitors into the cerebral white matter. Neurobiol Dis. 2011;44:19–27.PubMedCentralPubMed
13.
Virgintino D, Errede M, Rizzi M, Girolamo F, Strippoli M, Walchli T, et al. The CXCL12/CXCR4/CXCR7 ligand-receptor system regulates neuro-glio-vascular interactions and vessel growth during human brain development. J Inherit Metab Dis. 2013;36:455–66.CrossRefPubMed
14.
Li M, Ransohoff RM. Multiple roles of chemokine CXCL12 in the central nervous system: a migration from immunology to neurobiology. Prog Neurobiol. 2008;84:116–31.PubMedCentralCrossRefPubMed
15.
Dubovy P, Klusakova I, Svizenska I, Brazda V. Spatio-temporal changes of SDF1 and its CXCR4 receptor in the dorsal root ganglia following unilateral sciatic nerve injury as a model of neuropathic pain. Histochem Cell Biol. 2010;133:323–37.CrossRefPubMed
16.
Knerlich-Lukoschus F, von der Ropp-Brenner B, Lucius R, Mehdorn HM, Held-Feindt J. Spatiotemporal CCR1, CCL3(MIP-1alpha), CXCR4, CXCL12(SDF-1alpha) expression patterns in a rat spinal cord injury model of posttraumatic neuropathic pain. J Neurosurg Spine. 2011;14:583–97.PubMed
17.
Callewaere C, Banisadr G, Desarmenien MG, Mechighel P, Kitabgi P, Rostene WH, et al. The chemokine SDF-1/CXCL12 modulates the firing pattern of vasopressin neurons and counteracts induced vasopressin release through CXCR4. Proc Natl Acad Sci U S A. 2006;103:8221–6.PubMedCentralCrossRefPubMed
18.
Guyon A, Nahon JL. Multiple actions of the chemokine stromal cell-derived factor-1alpha on neuronal activity. J Mol Endocrinol. 2007;38:365–76.CrossRefPubMed
19.
Guyon A, Rovere C, Cervantes A, Allaeys I, Nahon JL. Stromal cell-derived factor-1alpha directly modulates voltage-dependent currents of the action potential in mammalian neuronal cells. J Neurochem. 2005;93:963–73.CrossRefPubMed
20.
Guyon A, Skrzydelsi D, Rovere C, Rostene W, Parsadaniantz SM, Nahon JL. Stromal cell-derived factor-1alpha modulation of the excitability of rat substantia nigra dopaminergic neurones: presynaptic mechanisms. J Neurochem. 2006;96:1540–50.CrossRefPubMed
21.
Oh SB, Tran PB, Gillard SE, Hurley RW, Hammond DL, Miller RJ. Chemokines and glycoprotein120 produce pain hypersensitivity by directly exciting primary nociceptive neurons. J Neurosci. 2001;21:5027–35.PubMed
22.
23.
Liu M, Wood JN. The roles of sodium channels in nociception: implications for mechanisms of neuropathic pain. Pain Med. 2011;12 Suppl 3:S93–9.CrossRefPubMed
24.
Dib-Hajj SD, Cummins TR, Black JA, Waxman SG. Sodium channels in normal and pathological pain. Annu Rev Neurosci. 2010;33:325–47.CrossRefPubMed
25.
Belkouch M, Dansereau MA, Tetreault P, Biet M, Beaudet N, Dumaine R, et al. Functional up-regulation of Nav1.8 sodium channel in Abeta afferent fibers subjected to chronic peripheral inflammation. J Neuroinflammation. 2014;11:45.PubMedCentralCrossRefPubMed
26.
He XH, Zang Y, Chen X, Pang RP, Xu JT, Zhou 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
27.
Liang L, Fan L, Tao B, Yaster M, Tao YX. Protein kinase B/Akt is required for complete Freund’s adjuvant-induced upregulation of Nav1.7 and Nav1.8 in primary sensory neurons. J Pain. 2013;14:638–47.PubMedCentralCrossRefPubMed
28.
Yu YQ, Zhao F, Guan SM, Chen J. Antisense-mediated knockdown of Na(V)1.8, but not Na(V)1.9, generates inhibitory effects on complete Freund’s adjuvant-induced inflammatory pain in rat. PLoS One. 2011;6:e19865.PubMedCentralCrossRefPubMed
29.
Yu YQ, Zhao ZY, Chen XF, Xie F, Yang Y, Chen J. Activation of tetrodotoxin-resistant sodium channel NaV1.9 in rat primary sensory neurons contributes to melittin-induced pain behavior. Neuromolecular Med. 2013;15:209–17.CrossRefPubMed
30.
Kao DJ, Li AH, Chen JC, Luo RS, Chen YL, Lu JC, et al. CC chemokine ligand 2 upregulates the current density and expression of TRPV1 channels and Nav1.8 sodium channels in dorsal root ganglion neurons. J Neuroinflammation. 2012;9:189.PubMedCentralCrossRefPubMed
31.
Wang JG, Strong JA, Xie W, Yang RH, Coyle DE, Wick DM, et al. The chemokine CXCL1/growth related oncogene increases sodium currents and neuronal excitability in small diameter sensory neurons. Mol Pain. 2008;4:38.PubMedCentralCrossRefPubMed
32.
Chen J, Chen HS. Pivotal role of capsaicin-sensitive primary afferents in development of both heat and mechanical hyperalgesia induced by intraplantar bee venom injection. Pain. 2001;91:367–76.CrossRefPubMed
33.
Chen J, Lariviere WR. The nociceptive and anti-nociceptive effects of bee venom injection and therapy: a double-edged sword. Prog Neurobiol. 2010;92:151–83.PubMedCentralCrossRefPubMed
34.
Chen J, Luo C, Li H, Chen H. Primary hyperalgesia to mechanical and heat stimuli following subcutaneous bee venom injection into the plantar surface of hindpaw in the conscious rat: a comparative study with the formalin test. Pain. 1999;83:67–76.CrossRefPubMed
35.
Yu YQ, Chen J. Activation of spinal extracellular signaling-regulated kinases by intraplantar melittin injection. Neurosci Lett. 2005;381:194–8.CrossRefPubMed
36.
Hao J, Liu MG, Yu YQ, Cao FL, Li Z, Lu ZM, et al. Roles of peripheral mitogen-activated protein kinases in melittin-induced nociception and hyperalgesia. Neuroscience. 2008;152:1067–75.CrossRefPubMed
37.
Mert T, Gunes Y. Antinociceptive activities of lidocaine and the nav1.8 blocker a803467 in diabetic rats. J Am Assoc Lab Anim Sci. 2012;51:579–85.PubMedCentralPubMed
38.
Moon JY, Song S, Yoon SY, Roh DH, Kang SY, Park JH, et al. The differential effect of intrathecal Nav1.8 blockers on the induction and maintenance of capsaicin- and peripheral ischemia-induced mechanical allodynia and thermal hyperalgesia. Anesth Analg. 2012;114:215–23.CrossRefPubMed
39.
Wu WP, Xu XJ, Hao JX. Chronic lumbar catheterization of the spinal subarachnoid space in mice. J Neurosci Methods. 2004;133:65–9.CrossRefPubMed
40.
Du Y, Xiao Y, Lu ZM, Ding J, Xie F, Fu H, et al. Melittin activates TRPV1 receptors in primary nociceptive sensory neurons via the phospholipase A2 cascade pathways. Biochem Biophys Res Commun. 2011;408:32–7.PubMedCentralCrossRefPubMed
41.
Yu YQ, Chen XF, Yang Y, Yang F, Chen J. Electrophysiological identification of tonic and phasic neurons in sensory dorsal root ganglion and their distinct implications in inflammatory pain. Physiol Res. 2014;63:793–9.PubMed
42.
Floridi F, Trettel F, Di Bartolomeo S, Ciotti MT, Limatola C. Signalling pathways involved in the chemotactic activity of CXCL12 in cultured rat cerebellar neurons and CHP100 neuroepithelioma cells. J Neuroimmunol. 2003;135:38–46.CrossRefPubMed
43.
Luo Y, Lathia J, Mughal M, Mattson MP. SDF1alpha/CXCR4 signaling, via ERKs and the transcription factor Egr1, induces expression of a 67-kDa form of glutamic acid decarboxylase in embryonic hippocampal neurons. J Biol Chem. 2008;283:24789–800.PubMedCentralCrossRefPubMed
44.
Lv B, Yang X, Lv S, Wang L, Fan K, Shi R, et al. CXCR4 Signaling induced epithelial-mesenchymal transition by PI3K/AKT and ERK pathways in glioblastoma. Mol Neurobiol. 2014;52:1263–68.CrossRefPubMed
45.
Chen J, Luo C, Li HL. The contribution of spinal neuronal changes to development of prolonged, tonic nociceptive responses of the cat induced by subcutaneous bee venom injection. Eur J Pain. 1998;2:359–76.CrossRefPubMed
46.
Chen J, Li H, Luo C, Li Z, Zheng J. Involvement of peripheral NMDA and non-NMDA receptors in development of persistent firing of spinal wide-dynamic-range neurons induced by subcutaneous bee venom injection in the cat. Brain Res. 1999;844:98–105.CrossRefPubMed
47.
Chen J, Guan S. Bee venom and pain. In: Gopalakrishnakone P, editor. Toxinology: Toxins and Drug Discovery. Springer, in press.
48.
Souza GR, Talbot J, Lotufo CM, Cunha FQ, Cunha TM, Ferreira SH. Fractalkine mediates inflammatory pain through activation of satellite glial cells. Proc Natl Acad Sci U S A. 2013;110:11193–8.PubMedCentralCrossRefPubMed
49.
Bhangoo SK, Ren D, Miller RJ, Chan DM, Ripsch MS, Weiss C, et al. CXCR4 chemokine receptor signaling mediates pain hypersensitivity in association with antiretroviral toxic neuropathy. Brain Behav Immun. 2007;21:581–91.PubMedCentralCrossRefPubMed
50.
Menichella DM, Abdelhak B, Ren D, Shum A, Frietag C, Miller RJ. CXCR4 chemokine receptor signaling mediates pain in diabetic neuropathy. Mol Pain. 2014;10:42.PubMedCentralCrossRefPubMed
51.
Wilson NM, Jung H, Ripsch MS, Miller RJ, White FA. CXCR4 signaling mediates morphine-induced tactile hyperalgesia. Brain Behav Immun. 2011;25:565–73.PubMedCentralCrossRefPubMed
52.
White FA, Sun J, Waters SM, Ma C, Ren D, Ripsch M, et al. 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;102:14092–7.PubMedCentralCrossRefPubMed
53.
Zhang N, Inan S, Cowan A, Sun R, Wang JM, Rogers TJ, et al. A proinflammatory chemokine, CCL3, sensitizes the heat- and capsaicin-gated ion channel TRPV1. Proc Natl Acad Sci U S A. 2005;102:4536–41.PubMedCentralCrossRefPubMed
54.
55.
Nodera H, Kaji R. Nerve excitability testing and its clinical application to neuromuscular diseases. Clin Neurophysiol. 2006;117:1902–16.CrossRefPubMed
56.
Andres C, Hasenauer J, Ahn HS, Joseph EK, Isensee J, Theis FJ, et al. Wound-healing growth factor, basic FGF, induces Erk1/2-dependent mechanical hyperalgesia. Pain. 2013;154:2216–26.CrossRefPubMed
57.
Belkouch M, Dansereau MA, Reaux-Le GA, Van Steenwinckel J, Beaudet N, Chraibi A, et al. The chemokine CCL2 increases Nav1.8 sodium channel activity in primary sensory neurons through a Gbetagamma-dependent mechanism. J Neurosci. 2011;31:18381–90.CrossRefPubMed
58.
Zhao R, Pei GX, Cong R, Zhang H, Zang CW, Tian T. PKC-NF-kappaB are involved in CCL2-induced Nav1.8 expression and channel function in dorsal root ganglion neurons. Biosci Rep. 2014;34(3):pii: e00111.CrossRef
59.
Shen KF, Zhu HQ, Wei XH, Wang J, Li YY, Pang RP, et al. Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Exp Neurol. 2013;247:466–75.CrossRefPubMed
60.
Akopian AN, Souslova V, England S, Okuse K, Ogata N, Ure J, et al. The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways. Nat Neurosci. 1999;2:541–8.CrossRefPubMed
61.
Han C, Estacion M, Huang J, Vasylyev DV, Zhao P, Dib-Hajj S, et al. Human Nav1.8: enhanced persistent and ramp currents contribute to distinct firing properties of human DRG neurons. J Neurophysiol. 2015;113:3172–85.CrossRefPubMed
62.
Liang J, Liu X, Pan M, Dai W, Dong Z, Wang X, et al. Blockade of Nav1.8 currents in nociceptive trigeminal neurons contributes to anti-trigeminovascular nociceptive effect of amitriptyline. Neuromolecular Med. 2014;16:308–21.CrossRefPubMed
63.
Abrahamsen B, Zhao J, Asante CO, Cendan CM, Marsh S, Martinez-Barbera JP, et al. The cell and molecular basis of mechanical, cold, and inflammatory pain. Science. 2008;321:702–5.CrossRefPubMed
64.
Zimmermann K, Leffler A, Babes A, Cendan CM, Carr RW, Kobayashi J, et al. Sensory neuron sodium channel Nav1.8 is essential for pain at low temperatures. Nature. 2007;447:855–8.CrossRefPubMed
65.
Jarvis MF, Honore P, Shieh CC, Chapman M, Joshi S, Zhang XF, et al. A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. Proc Natl Acad Sci U S A. 2007;104:8520–5.PubMedCentralCrossRefPubMed
66.
Dib-Hajj SD, Binshtok AM, Cummins TR, Jarvis MF, Samad T, Zimmermann K. Voltage-gated sodium channels in pain states: role in pathophysiology and targets for treatment. Brain Res Rev. 2009;60:65–83.CrossRefPubMed
67.
England S. Voltage-gated sodium channels: the search for subtype-selective analgesics. Expert Opin Investig Drugs. 2008;17:1849–64.CrossRefPubMed
68.
Dworkin RH, O’Connor AB, Audette J, Baron R, Gourlay GK, Haanpaa ML, et al. Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc. 2010;85:S3–14.PubMedCentralCrossRefPubMed
Metadata
Title
SDF1–CXCR4 signaling contributes to persistent pain and hypersensitivity via regulating excitability of primary nociceptive neurons: involvement of ERK-dependent Nav1.8 up-regulation
Authors
Fei Yang
Wei Sun
Yan Yang
Yan Wang
Chun-Li Li
Han Fu
Xiao-Liang Wang
Fan Yang
Ting He
Jun Chen
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2015
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-015-0441-2

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