Hostname: page-component-cd9895bd7-fscjk Total loading time: 0 Render date: 2024-12-27T19:09:05.721Z Has data issue: false hasContentIssue false
  • English
  • Français

Involvement of calcitonin gene-related peptide and CCL2 production in CD40-mediated behavioral hypersensitivity in a model of neuropathic pain

Published online by Cambridge University Press:  01 March 2012

Jennifer T. Malon ,
Swathi Maddula ,
Harmony Bell  and
Ling Cao
Jennifer T. Malon
Affiliation:
Department of Microbiology, Biomedical Sciences Section, College of Osteopathic Medicine, University of New England, Biddeford, ME 04005, USA
Swathi Maddula
Affiliation:
Department of Microbiology, Biomedical Sciences Section, College of Osteopathic Medicine, University of New England, Biddeford, ME 04005, USA
Harmony Bell
Affiliation:
Department of Microbiology, Biomedical Sciences Section, College of Osteopathic Medicine, University of New England, Biddeford, ME 04005, USA
Ling Cao*
Affiliation:
Department of Microbiology, Biomedical Sciences Section, College of Osteopathic Medicine, University of New England, Biddeford, ME 04005, USA
*
Correspondence should be addressed to: Ling Cao, Department of Microbiology, Biomedical Sciences Section, College of Osteopathic Medicine, University of New England, Biddeford, ME 04005, USA phone: +1 207 602 2213 fax: +1 207 602 5931 email: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

The neuropeptide calcitonin gene-related peptide (CGRP) is known to play a pro-nociceptive role after peripheral nerve injury upon its release from primary afferent neurons in preclinical models of neuropathic pain. We previously demonstrated a critical role for spinal cord microglial CD40 in the development of spinal nerve L5 transection (L5Tx)-induced mechanical hypersensitivity. Herein, we investigated whether CGRP is involved in the CD40-mediated behavioral hypersensitivity. First, L5Tx was found to significantly induce CGRP expression in wild-type (WT) mice up to 14 days post-L5Tx. This increase in CGRP expression was reduced in CD40 knockout (KO) mice at day 14 post-L5Tx. Intrathecal injection of the CGRP antagonist CGRP8–37 significantly blocked L5Tx-induced mechanical hypersensitivity. In vitro, CGRP induced glial IL-6 and CCL2 production, and CD40 stimulation added to the effects of CGRP in neonatal glia. Further, there was decreased CCL2 production in CD40 KO mice compared to WT mice 21 days post-L5Tx. However, CGRP8–37 did not significantly affect spinal cord CCL2 production following L5Tx in WT mice. Altogether, these data suggest that CD40 contributes to the maintenance of behavioral hypersensitivity following peripheral nerve injury in part through two distinct pathways, the enhancement of CGRP expression and spinal cord CCL2 production.

Keywords

Spinal nerve L5 transectiongliachemokinecytokineCCL2
Type
Research Article
Information
Neuron Glia Biology , Volume 7 , Issue 2-4 , May 2011 , pp. 117 - 128
Copyright
Copyright © Cambridge University Press 2012

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

Abbadie, C., Lindia, J.A., Cumiskey, A.M., Peterson, L.B., Mudgett, J.S., Bayne, E.K. et al. (2003) Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2. Proceedings of the National Academy of Sciences of the U.S.A. 100, 7947–7952.Google Scholar
Ait-Ghezala, G., Mathura, V.S., Laporte, V., Quadros, A., Paris, D., Patel, N. et al. (2005) Genomic regulation after CD40 stimulation in microglia: relevance to Alzheimer's disease. Brain Research Molecular Brain Research 140, 73–85.Google Scholar
Arulmani, U., MaassenVanDenBrink, A., Villalón, C.M. and Saxena, P.R. (2004) Calcitonin gene-related peptide and its role in migraine pathophysiology. European Journal of Pharmacology 500, 315–330.Google Scholar
Becher, B., Blain, M. and Antel, J.P. (2000) CD40 engagement stimulates IL-12 p70 production by human microglial cells: basis for Th1 polarization in the CNS. Journal of Neuroimmunology 102, 44–50.Google Scholar
Becher, B., Durell, B.G., Miga, A.V., Hickey, W.F. and Noelle, R.J. (2001) The clinical course of experimental autoimmune encephalomyelitis and inflammation is controlled by the expression of CD40 within the central nervous system. Journal of Experimental Medicine 193, 967–974.Google Scholar
Bennett, A.D., Chastain, K.M. and Hulsebosch, C.E. (2000) Alleviation of mechanical and thermal allodynia by CGRP8-37 in a rodent model of chronic central pain. Pain 86, 163–175.Google Scholar
Benveniste, E.N., Nguyen, V.T. and O'Keefe, G.M. (2001) Immunological aspects of microglia: relevance to Alzheimer's disease. Neurochemistry International 39, 381–391.Google Scholar
Callewaere, C., Banisadr, G., Rostene, W. and Parsadaniantz, S.M. (2007) Chemokines and chemokine receptors in the brain: implication in neuroendocrine regulation. Journal of Molecular Endocrinology 38, 355–363.Google Scholar
Cao, L. and DeLeo, J.A. (2008) CNS-infiltrating CD4+ T lymphocytes contribute to murine spinal nerve transection-induced neuropathic pain. European Journal Immunology 38, 448–458.Google Scholar
Cao, L., Fei, L., Chang, T.T. and DeLeo, J.A. (2007) Induction of interleukin-1beta by interleukin-4 in lipopolysaccharide-treated mixed glial cultures: microglial-dependent effects. Journal of Neurochemistry 102, 408–419.Google Scholar
Cao, L., Palmer, C.D., Malon, J.T. and De Leo, J.A. (2009a) Critical role of microglial CD40 in the maintenance of mechanical hypersensitivity in a murine model of neuropathic pain. European Journal of Immunology 39, 3562–3569.Google Scholar
Cao, L., Tanga, F.Y. and Deleo, J.A. (2009b) The contributing role of CD14 in toll-like receptor 4 dependent neuropathic pain. Neuroscience 158, 896–903.CrossRefGoogle ScholarPubMed
Chabot, S., Williams, G., Hamilton, M., Sutherland, G. and Yong, V.W. (1999) Mechanisms of IL-10 production in human microglia-T cell interaction. Journal of Immunology 162, 6819–6828.Google Scholar
Chaplan, S.R., Bach, F.W., Pogrel, J.W., Chung, J.M. and Yaksh, T.L. (1994) Quantitative assessment of tactile allodynia in the rat paw. Journal of Neuroscience Methods 53, 55–63.Google Scholar
Chen, L.J., Zhang, F.G., Li, J., Song, H.X., Zhou, L.B., Yao, B.C. et al. (2010) Expression of calcitonin gene-related peptide in anterior and posterior horns of the spinal cord after brachial plexus injury. Journal of Clinical Neuroscience 17, 87–91.Google Scholar
Dalpke, A.H., Schafer, M.K., Frey, M., Zimmermann, S., Tebbe, J., Weihe, E. et al. (2002) Immunostimulatory CpG-DNA activates murine microglia. Journal of Immunology 168, 4854–4863.Google Scholar
D'Aversa, T.G., Weidenheim, K.M. and Berman, J.W. (2002) CD40–CD40L interactions induce chemokine expression by human microglia: implications for human immunodeficiency virus encephalitis and multiple sclerosis. American Journal of Pathology 160, 559–567.Google Scholar
DeLeo, J.A., Tanga, F.Y. and Tawfik, V.L. (2004) Neuroimmune activation and neuroinflammation in chronic pain and opioid tolerance/hyperalgesia. Neuroscientist 10, 40–52.Google Scholar
Gao, Y.J. and Ji, R.R. (2010) Chemokines, neuronal-glial interactions, and central processing of neuropathic pain. Pharmacological Therapy 126, 56–68.Google Scholar
Gao, Y.J., Zhang, L., Samad, O.A., Suter, M.R., Yasuhiko, K., Xu, Z.Z. et al. (2009) JNK-induced MCP-1 production in spinal cord astrocytes contributes to central sensitization and neuropathic pain. Journal of Neuroscience 29, 4096–4108.Google Scholar
Gardell, L.R., Vanderah, T.W., Gardell, S.E., Wang, R., Ossipov, M.H., Lai, J. et al. (2003) Enhanced evoked excitatory transmitter release in experimental neuropathy requires descending facilitation. Journal of Neuroscience 23, 8370–8379.Google Scholar
Garside, P., Ingulli, E., Merica, R.R., Johnson, J.G., Noelle, R.J. and Jenkins, M.K. (1998) Visualization of specific B and T lymphocyte interactions in the lymph node. Science 281, 96–99.Google Scholar
Greter, M., Heppner, F.L., Lemos, M.P., Odermatt, B.M., Goebels, N., Laufer, T. et al. (2005) Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis. Nature Medicine 11, 328–334.Google Scholar
Grewal, I.S. and Flavell, R.A. (1998) CD40 and CD154 in cell-mediated immunity. Annual Review of Immunology 16, 111–135.Google Scholar
Hickey, W.F., Vass, K. and Lassmann, H. (1992) Bone marrow-derived elements in the central nervous system: an immunohistochemical and ultrastructural survey of rat chimeras. Journal of Neuropathology and Experimental Neurology 51, 246–256.Google Scholar
Hudson, C.A., Christophi, G.P., Gruber, R.C., Wilmore, J.R., Lawrence, D.A. and Massa, P.T. (2008) Induction of IL-33 expression and activity in central nervous system glia. Journal of Leukocyte Biology 84, 631–643.Google Scholar
Jana, M., Liu, X., Koka, S., Ghosh, S., Petro, T.M. and Pahan, K. (2001) Ligation of CD40 stimulates the induction of nitric-oxide synthase in microglial cells. Journal of Biological Chemistry 276, 44527–44533.Google Scholar
Jensen, T.S., Baron, R., Haanpãã, M., Kalso, E., Loeser, J.D., Rice, A.S.C. et al. (2011) A new definition of neuropathic pain. Pain 152, 2204–2205.Google Scholar
Lee, S.E. and Kim, J.-H. (2007) Involvement of substance P and calcitonin gene-related peptide in development and maintenance of neuropathic pain from spinal nerve injury model of rat. Neuroscience Research 58, 245–249.Google Scholar
Li, J., Vause, C.V. and Durham, P.L. (2008) Calcitonin gene-related peptide stimulation of nitric oxide synthesis and release from trigeminal ganglion glial cells. Brain Research 1196, 22–32.Google Scholar
Matyszak, M.K., Denis-Donini, S., Citterio, S., Longhi, R., Granucci, F. and Ricciardi-Castagnoli, P. (1999) Microglia induce myelin basic protein-specific T cell anergy or T cell activation, according to their state of activation. European Journal of Immunology 29, 3063–3076.Google Scholar
Milligan, E.D. and Watkins, L.R. (2009) Pathological and protective roles of glia in chronic pain. Nature Review of Neuroscience 10, 23–36.Google Scholar
Moalem, G. and Tracey, D.J. (2006) Immune and inflammatory mechanisms in neuropathic pain. Brain Research Review 51, 240–264.Google Scholar
Okuno, T., Nakatsuji, Y., Kumanogoh, A., Koguchi, K., Moriya, M., Fujimura, H. et al. (2004) Induction of cyclooxygenase-2 in reactive glial cells by the CD40 pathway: relevance to amyotrophic lateral sclerosis. Journal of Neurochemistry 91, 404–412.Google Scholar
Olson, J.K., Girvin, A.M. and Miller, S.D. (2001) Direct activation of innate and antigen-presenting functions of microglia following infection with Theiler's virus. Journal of Virology 75, 9780–9789.Google Scholar
Piehl, F., Arvidsson, U., Johnson, H., Cullheim, S., Villar, M., Dagerlind, A. et al. (1991) Calcitonin gene-related peptide (CGRP)-like immunoreactivity and CGRP mRNA in rat spinal cord motoneurons after different types of lesions. European Journal of Neuroscience 3, 737–757.Google Scholar
Piehl, F., Hammarberg, H., Tabar, G., Hokfelt, T. and Cullheim, S. (1998) Changes in the mRNA expression pattern, with special reference to calcitonin gene-related peptide, after axonal injuries in rat motoneurons depends on age and type of injury. Experimental Brain Research 119, 191–204.Google Scholar
Ponomarev, E.D., Shriver, L.P., Maresz, K. and Dittel, B.N. (2005) Microglial cell activation and proliferation precedes the onset of CNS autoimmunity. Journal of Neuroscience Research 81, 374–389.Google Scholar
Priller, J., Haas, C.A., Reddington, M. and Kreutzberg, G.W. (1995) Calcitonin gene-related peptide and ATP induce immediate early gene expression in cultured rat microglial cells. Glia 15, 447–457.Google Scholar
Reddington, M., Priller, J., Treichel, J., Haas, C. and Kreutzberg, G.W. (1995) Astrocytes and microglia as potential targets for calcitonin gene related peptide in the central nervous system. Canadian Journal of Physiology and Pharmacology 73, 1047–1049.Google Scholar
Tan, J., Town, T., Paris, D., Mori, T., Suo, Z., Crawford, F. et al. (1999a) Microglial activation resulting from CD40-CD40L interaction after beta-amyloid stimulation. Science 286, 2352–2355.Google Scholar
Tan, J., Town, T., Paris, D., Placzek, A., Parker, T., Crawford, F. et al. (1999b) Activation of microglial cells by the CD40 pathway: relevance to multiple sclerosis. Journal of Neuroimmunology 97, 77–85.Google Scholar
Tawfik, V.L., Lacroix-Fralish, M.L., Bercury, K.K., Nutile-McMenemy, N., Harris, B.T. and Deleo, J.A. (2006) Induction of astrocyte differentiation by propentofylline increases glutamate transporter expression in vitro: heterogeneity of the quiescent phenotype. Glia 54, 193–203.Google Scholar
Togo, T., Akiyama, H., Kondo, H., Ikeda, K., Kato, M., Iseki, E. et al. (2000) Expression of CD40 in the brain of Alzheimer's disease and other neurological diseases. Brain Research 885, 117–121.Google Scholar
Tsuda, M., Inoue, K. and Salter, M.W. (2005) Neuropathic pain and spinal microglia: a big problem from molecules in ‘small’ glia. Trends in Neuroscience 28, 101–107.Google Scholar
Weihe, E., Nohr, D., Schafer, M.K., Persson, S., Ekstrom, G., Kallstrom, J. et al. (1995) Calcitonin gene related peptide gene expression in collagen-induced arthritis. Canadian Journal of Physiology and Pharmacology 73, 1015–1019.Google Scholar
White, F.A., Jung, H. and Miller, R.J. (2007) Chemokines and the pathophysiology of neuropathic pain. Proceedings of the National Academy of Sciences of the U.S.A. 104, 20151–20158.Google Scholar
White, F.A., Sun, J., Waters, S.M., Ma, C., Ren, D., Ripsch, M. et al. (2005) Excitatory monocyte chemoattractant protein-1 signaling is up-regulated in sensory neurons after chronic compression of the dorsal root ganglion. Proceedings of the National Academy of Sciences of the U.S.A 102, 14092–14097.Google Scholar
Yu, L.C., Hansson, P. and Lundeberg, T. (1996) The calcitonin gene-related peptide antagonist CGRP8-37 increases the latency to withdrawal responses bilaterally in rats with unilateral experimental mononeuropathy, an effect reversed by naloxone. Neuroscience 71, 523–531.Google Scholar
Zhang, J. and De Koninck, Y. (2006) Spatial and temporal relationship between monocyte chemoattractant protein-1 expression and spinal glial activation following peripheral nerve injury. Journal of Neurochemistry 97, 772–783.Google Scholar
Zhang, J., Shi, X.Q., Echeverry, S., Mogil, J.S., De Koninck, Y. and Rivest, S. (2007) Expression of CCR2 in both resident and bone marrow-derived microglia plays a critical role in neuropathic pain. Journal of Neuroscience 27, 12396–12406.Google Scholar
Zheng, L.F., Wang, R., Xu, Y.Z., Yi, X.N., Zhang, J.W. and Zeng, Z.C. (2008) Calcitonin gene-related peptide dynamics in rat dorsal root ganglia and spinal cord following different sciatic nerve injuries. Brain Research 1187, 20–32.Google Scholar