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Involvement of Spinal Chemokine CCL2 in the Hyperalgesia Evoked by Bone Cancer in Mice: A Role for Astroglia and Microglia

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Abstract

The hypernociceptive role played by the chemokine CCL2, and its main receptor, CCR2, in pathological settings is being increasingly recognized. We aimed to characterize the involvement of spinal CCL2 in the hyperalgesia due to the intratibial inoculation of fibrosarcoma NCTC 2472 cells in mice. The intrathecal (i.t.) administration of the CCR2 antagonist RS 504393 (1–3 μg) or an anti-CCL2 antibody inhibited tumoral hyperalgesia. No change in the expression of spinal CCR2 was detected by western blot, whereas immunohistochemical experiments demonstrated increased CCL2 staining at the superficial laminae of the spinal cord ipsilateral to the tumor. This spinal CCL2 does not seem to be released from nociceptors since CCL2 mRNA and CCL2 levels in DRGs, as measured by RT-PCR and ELISA, remain unmodified in tumor-bearing mice. In contrast, immunohistochemical assays demonstrated the spinal up-regulations of GFAP and Iba-1, respective markers of astroglia and microglia, and the expression of CCL2 in both types of glial cells at the superficial laminae of the spinal cord of tumor-bearing mice. Finally, since CCL2 could induce astroglial or microglial activation, we studied whether the blockade of CCR2 could inhibit the increased spinal glial expression. GFAP, but not Iba-1, up-regulation was reduced in tumor-bearing mice treated for 3 days with i.t. RS 504393, indicating that spinal CCL2 acts as an astroglial activator in this setting. The participation at spinal level of CCL2/CCR2 in tumoral hypernociception, together with its previously described involvement at periphery, makes attractive the modulation of this system for the alleviation of neoplastic pain.

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Acknowledgments

Grants were provided by MEC (SAF2012-36271). M.P. is the recipient of a grant from the Instituto Universitario de Oncología (IUOPA). IUOPA is supported by Obra Social Cajastur-Asturias, Spain. The authors appreciate the excellent technical assistance given by Marta Alonso Guervós and Ángel Martínez Nistal (Servicios Científico-Técnicos, Universidad de Oviedo) for fluorescence microscopy and imaging processing.

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The authors declare that they have no conflict of interest

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  1. Sara González-Rodríguez

    Present address: Department of Anesthesiology and Critical Care Medicine, Charité Campus Benjamin Franklin, Freie Universität Berlin, Hindenburgdamm 30, 12200, Berlin, Germany

Authors and Affiliations

  1. Laboratorio de Farmacología, Facultad de Medicina, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, c/ Julián Clavería 6, 33006, Oviedo, Asturias, Spain

    Marta Pevida, Sara González-Rodríguez, Ana Lastra, Agustín Hidalgo, Luis Menéndez & Ana Baamonde

  2. Departamento de Morfologia y Biologia Celular, Facultad de Medicina, Universidad de Oviedo, c/ Julián Clavería 6, 33006, Oviedo, Asturias, Spain

    Olivia García-Suárez

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  1. Marta Pevida
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Correspondence to Ana Baamonde.

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Pevida, M., González-Rodríguez, S., Lastra, A. et al. Involvement of Spinal Chemokine CCL2 in the Hyperalgesia Evoked by Bone Cancer in Mice: A Role for Astroglia and Microglia. Cell Mol Neurobiol 34, 143–156 (2014). https://doi.org/10.1007/s10571-013-9995-7

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