Role of spinal microglia in rat models of peripheral nerve injury and inflammation Anna K. Clark a,b , Clive Gentry b , Elizabeth J. Bradbury a , Stephen B. McMahon a , Marzia Malcangio a,b, * a Neurorestoration, Wolfson Centre for Age Related Diseases, King’s College London, Wolfson Wing, Hodgkin Building, Guys Campus, London SE1 1UL, UK b Chronic Pain Programme, Neuroscience, Novartis Institutes for Biomedical Research, London, UK Received 15 September 2005; received in revised form 19 January 2006; accepted 6 February 2006 Available online 20 March 2006 Abstract Mounting evidence supports the hypothesis that spinal microglia modulate the development and maintenance of some chronic pain states. Here we examined the role of spinal microglia following both peripheral inflammatory insult and peripheral nerve injury. We observed significant ipsilateral dorsal horn microglia activation 2 weeks after injury and bilateral activation 50 days following nerve injury as well as 24 h following intraplantar zymosan but not intraplantar complete Freund’s adjuvant (CFA). Ipsilateral but not contralateral microglia activation was associated with hind paw mechanical hyperalgesia. Spinal injection of the glial metabolic inactivator fluorocitrate attenuated ipsilateral hyperalgesia and bilateral spinal microglia activation after peripheral nerve injury. Intrathecal fluorocitrate reversed hyperalgesia after intraplantar zymosan and produced no reversal of CFA-induced hyperalgesia. These data suggest a role for spinal glia in the persistence of mechanical hyperalgesia following peripheral nerve injury. However, activation of spinal microglia contralaterally did not correlate to nociception. Furthermore, it would appear that the time course of microglia activation and their contribution to inflammatory pain is dependent on the inflammatory stimulus administered. Ó 2006 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved. Keywords: Neuropathy; Zymosan; CFA; Hyperalgesia; OX42 1. Introduction The complexity of both inflammatory and neuro- pathic pain states is represented by the vast number of molecules that have so far been implicated in alterations in nociceptive transmission following injury. Mounting evidence supports the hypothesis that microglia, the res- ident macrophages of the central nervous system, play a role in modulating neuronal changes in the development and maintenance of a number of chronic pain states (Araque et al., 1999; DeLeo and Yezierski, 2001; Wat- kins and Maier, 2003; Tsuda et al., 2005). Resident microglia in the spinal cord respond quickly to injury of the nervous system, upregulating the synthesis and expression of cell surface receptors and increasing the release of a variety of proinflammatory cytokines including interleukin1b and tumour necrosis factor a (Chauvet et al., 2001; Marchand et al., 2005; McMahon et al., 2005; Tsuda et al., 2005). This occurs in concom- itance to dramatic changes within neurones in the dorsal 1090-3801/$32 Ó 2006 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpain.2006.02.003 * Corresponding author. Tel.: +44 02084848141; fax: +44 0208486165. E-mail address: marzia.malcangio@kcl.ac.uk (M. Malcangio). www.EuropeanJournalPain.com European Journal of Pain 11 (2007) 223–230