Present address: Institut de la Vision, UMR S 968 INSERM, UMR 7210 CNRS, Université Pierre et Marie Curie, 17 Rue Moreau, 75012 Paris, France.
Cellular and subcellular localization of CXCL12 and CXCR4 in rat nociceptive structures: physiological relevance
Article first published online: 14 JUN 2012
© 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd
European Journal of Neuroscience
Volume 36, Issue 5, pages 2619–2631, September 2012
How to Cite
Reaux-Le Goazigo, A., Rivat, C., Kitabgi, P., Pohl, M. and Melik Parsadaniantz, S. (2012), Cellular and subcellular localization of CXCL12 and CXCR4 in rat nociceptive structures: physiological relevance. European Journal of Neuroscience, 36: 2619–2631. doi: 10.1111/j.1460-9568.2012.08179.x
- Issue published online: 3 SEP 2012
- Article first published online: 14 JUN 2012
- Received 12 December 2011, revised 3 May 2012, accepted 4 May 2012
- chemokine receptors;
- electron microscopy;
- mechanical hypersensitivity;
- sensory neurons
Initial studies implicated the chemokine CXC motif ligand 12 (CXCL12) and its cognate CXC motif receptor 4 (CXCR4) in pain modulation. However, there has been no description of the distribution, transport and axonal sorting of CXCL12 and CXCR4 in rat nociceptive structures, and their direct participation in nociception modulation has not been demonstrated. Here, we report that acute intrathecal administration of CXCL12 induced mechanical hypersensitivity in naive rats. This effect was prevented by a CXCR4-neutralizing antibody. To determine the morphological basis of this behavioural response, we used light and electron microscopic immunohistochemistry to map CXCL12- and CXCR4-immunoreactive elements in dorsal root ganglia, lumbar spinal cord, sciatic nerve and skin. Light microscopy analysis revealed CXCL12 and CXCR4 immunoreactivity in calcitonin gene related peptide-containing peptidergic primary sensory neurons, which were both conveyed to central and peripheral sensory nerve terminals. Electron microscopy clearly demonstrated CXCL12 and CXCR4 immunoreactivity in primary sensory nerve terminals in the dorsal horn; both were sorted into small clear vesicles and large dense-core vesicles. This suggests that CXCL12 and CXCR4 are trafficked from nerve cell bodies to the dorsal horn. Double immunogold labelling for CXCL12 and calcitonin gene related peptide revealed partial vesicular colocalization in axonal terminals. We report, for the first time, that CXCR4 receptors are mainly located on the neuronal plasma membrane, where they are present at pre-synaptic and post-synaptic sites of central terminals. Receptor inactivation experiments, behavioural studies and morphological analyses provide strong evidence that the CXCL12/CXCR4 system is involved in modulation of nociceptive signalling.