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The Journal of Neuroscience, February 1, 2003, 23(3):1026

Spinal Glia and Proinflammatory Cytokines Mediate Mirror-Image Neuropathic Pain in Rats

Erin D. Milligan¹, Carin Twining¹, Marucia Chacur², Joseph Biedenkapp¹, Kevin O'Connor¹, Stephen Poole³, Kevin Tracey⁴, David Martin⁵, Steven F. Maier¹, and Linda R. Watkins¹

¹ Department of Psychology and the Center for Neuroscience, University of Colorado at Boulder, Boulder, Colorado 80309-0345, ² Laboratory of Pathophysiology, Butantan Institute, 05503-900, San Paulo, SP, Brazil,³ Division of Endocrinology, National Institute for Biological Standards and Control, South Mimms, Potters Bar, Herts EN6 3QG, United Kingdom, ⁴ Laboratory of Biomedical Science, North Shore-LIJ Research Institute, Manhasset, New York 11030, and ⁵ Department of Pharmacology, Amgen, Thousand Oaks, California 91320

Mirror-image allodynia is a mysterious phenomenon that occurs in association with many clinical pain syndromes. Allodynia refers to pain in response to light touch/pressure stimuli, which normally are perceived as innocuous. Mirror-image allodynia arises from the healthy body region contralateral to the actual site of trauma/inflammation. Virtually nothing is known about the mechanisms underlying such pain. A recently developed animal model of inflammatory neuropathy reliably produces mirror-image allodynia, thus allowing this pain phenomenon to be analyzed. In this sciatic inflammatory neuropathy (SIN) model, decreased response threshold to tactile stimuli (mechanical allodynia) develops in rats after microinjection of immune activators around one healthy sciatic nerve at mid-thigh level. Low level immune activation produces unilateral allodynia ipsilateral to the site of sciatic inflammation; more intense immune activation produces bilateral (ipsilateral + mirror image) allodynia. The present studies demonstrate that both ipsilateral and mirror-image SIN-induced allodynias are (1) reversed by intrathecal (peri-spinal) delivery of fluorocitrate, a glial metabolic inhibitor; (2) prevented and reversed by intrathecal CNI-1493, an inhibitor of p38 mitogen-activated kinases implicated in proinflammatory cytokine production and signaling; and (3) prevented or reversed by intrathecal proinflammatory cytokine antagonists specific for interleukin-1, tumor necrosis factor, or interleukin-6. Reversal of ipsilateral and mirror-image allodynias was rapid and complete even when SIN was maintained constantly for 2 weeks before proinflammatory cytokine antagonist administration. These results provide the first evidence that ipsilateral and mirror-image inflammatory neuropathy pain are created both acutely and chronically through glial and proinflammatory cytokine actions.

Key words: microglia; astrocyte; interleukin-1; tumor necrosis factor; interleukin-6; allodynia; p38 MAP kinase

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Copyright © 2003 Society for Neuroscience  0270-6474/03/2331026-15$05.00/0

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