Role of PAF Receptor in Proinflammatory Cytokine Expression in the Dorsal Root Ganglion and Tactile Allodynia in a Rodent Model of Neuropathic Pain Shigeo Hasegawa 1 , Yuta Kohro1, Miho Shiratori1, Satoshi Ishii2, Takao Shimizu2, Makoto Tsuda1, Kazuhide Inoue1* 1 Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan, 2 Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan Abstract Background: Neuropathic pain is a highly debilitating chronic pain following damage to peripheral sensory neurons and is often resistant to all treatments currently available, including opioids. We have previously shown that peripheral nerve injury induces activation of cytosolic phospholipase A2 (cPLA2) in injured dorsal root ganglion (DRG) neurons that contribute to tactile allodynia, a hallmark of neuropathic pain. However, lipid mediators downstream of cPLA2 activation to produce tactile allodynia remain to be determined. Principal Findings: Here we provide evidence that platelet-activating factor (PAF) is a potential candidate. Pharmacological blockade of PAF receptors (PAFRs) reduced the development and expression of tactile allodynia following nerve injury. The expression of PAFR mRNA was increased in the DRG ipsilateral to nerve injury, which was seen mainly in macrophages. Furthermore, mice lacking PAFRs showed a reduction of nerve injury-induced tactile allodynia and, interestingly, a marked suppression of upregulation of tumor necrosis factor a (TNFa) and interleukin-1b (IL-1b) expression in the injured DRG, crucial proinflammatory cytokines involved in pain hypersensitivity. Conversely, a single injection of PAF near the DRG of na¨ıve rats caused a decrease in the paw withdrawal threshold to mechanical stimulation in a dose-dependent manner and an increase in the expression of mRNAs for TNFa and IL-1b, both of which were inhibited by pretreatment with a PAFR antagonist. Conclusions: Our results indicate that the PAF/PAFR system has an important role in production of TNFa and IL-1b in the DRG and tactile allodynia following peripheral nerve injury and suggest that blocking PAFRs may be a viable therapeutic strategy for treating neuropathic pain. Citation: Hasegawa S, Kohro Y, Shiratori M, Ishii S, Shimizu T, et al. (2010) Role of PAF Receptor in Proinflammatory Cytokine Expression in the Dorsal Root Ganglion and Tactile Allodynia in a Rodent Model of Neuropathic Pain. PLoS ONE 5(5): e10467. doi:10.1371/journal.pone.0010467 Editor: Louis S. Premkumar, Southern Illinois University School of Medicine, United States of America Received October 7, 2009; Accepted April 10, 2010; Published May 3, 2010 Copyright: 2010 Hasegawa et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (#20689030 to MT, #18GS0319 to KI). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: inoue@phar.kyushu-u.ac.jp Introduction Neuropathic pain that occurs after nerve injury results from an aberrant functioning of a pathologically altered nervous system [1,2]. A hallmark of neuropathic pain syndrome is tactile allodynia, an abnormal hypersensitivity to innocuous stimuli, which is often resistant to all treatments currently available, including potent analgesic opioid drugs. The underlying mecha- nisms by which nerve injury develops tactile allodynia have remained largely unknown. The dorsal root ganglion (DRG) contains cell bodies of primary afferent neurons that transmit sensory information from the periphery to the central nervous system. The activation of signal transduction cascades and the transcriptional changes in the DRG and the resultant alterations in the transmission properties of sensory neurons following peripheral nerve injury might be involved in modulation of pain signaling in acute and chronic pain conditions [2,3]. We have previously shown that peripheral nerve injury induces activation of cytosolic phospholipase A2 (cPLA2), a Ca2+- dependent subclass of the PLA2 family [4] that is required for tactile allodynia [5], in DRG neurons. However, the way in which activated cPLA2 participates in tactile allodynia remains unknown. cPLA2 is a crucial enzyme that catalyzes the hydrolysis of phospholipids to release arachidonic acid and lysophospholipid, and subsequently generates lipid mediators. Arachidonic acid is metabolized to prostaglandins by the cyclooxygenase (COX) pathway and to leukotrienes by the lipoxygenase (LOX) pathway. Lysophospholipid can be converted to platelet-activating factor (PAF) by lyso-PAF acetyltransferase and to lysophosphatidic acid (LPA) by lysophospholipase D. It raises the possibility that these lipid mediators mediated by cPLA2 activation may be secreted from DRG neurons and, in turn, may modulate the excitation of DRG neurons directly or indirectly. Indeed, prostaglandins have been shown to cause sensitization of peripheral sensory neurons PLoS ONE | www.plosone.org 1 May 2010 | Volume 5 | Issue 5 | e10467