Review Pain and purinergic signaling Makoto Tsuda, Hidetoshi Tozaki-Saitoh, Kazuhide Inoue ⁎ Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi, Fukuoka 812-8582, Japan ARTICLE INFO ABSTRACT Article history: Accepted 11 November 2009 Available online 18 November 2009 A growing body of evidence indicates that extracellular nucleotides play important roles in the regulation of neuronal and glial functions in the nervous system through P2 purinoceptors. P2 purinoceptors are divided into two families, ionotropic receptors (P2X) and metabotropic receptors (P2Y). P2X receptors (seven types; P2X1–P2X7) contain intrinsic pores that open by binding with ATP, and P2Y receptors (eight types; P2Y1, 2, 4, 6, 11, 12, 13 and 14) are activated by nucleotides and couple to intracellular second-messenger systems through heterotrimeric G-proteins. Nucleotides are released or leaked from non-excitable cells as well as neurons in physiological and pathophysiological conditions. Studies have shown that microglia, a type of glial cells known as resident macrophages in the CNS, express several subtypes of P2X and P2Y receptors, and these receptors play a key role in pain signaling in the spinal cord under pathological conditions such as by peripheral nerve injury (called neuropathic pain). Within the spinal dorsal horn, peripheral nerve injury leads to a progressive series of changes in microglia including morphological hypertrophy of the cell body and proliferation, which are considered indicative of activation. These activated microglia upregulate expression of P2X/Y receptors (e.g., P2X4 and P2Y12). Importantly, pharmacological, molecular and genetic manipulations of the function or expression of these microglial molecules strongly suppress neuropathic pain. We expect that further investigation to determine how ATP signaling via P2X receptors participates in the pathogenesis of chronic pain will lead to a better understanding of the molecular mechanisms of pathological pain and provide clues for the development of new therapeutic drugs. © 2009 Elsevier B.V. All rights reserved. Keywords: Purinoceptor Neuropathic pain Microglia Spinal cord Contents 1. Introduction .......................................................... 223 2. Molecular structure and pharmacological profiles of purinergic receptors ........................ 224 2.1. P2X receptors ..................................................... 224 2.2. P2Y receptors ..................................................... 224 3. Purinergic signaling and neuropathic pain ......................................... 225 3.1. P2X4 receptor ..................................................... 225 3.2. P2X7 receptor ..................................................... 227 BRAIN RESEARCH REVIEWS 63 (2010) 222 – 232 ⁎ Corresponding author. Fax: +81 92 642 4729. E-mail address: inoue@phar.kyushu-u.ac.jp (K. Inoue). 0165-0173/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.brainresrev.2009.11.003 available at www.sciencedirect.com www.elsevier.com/locate/brainresrev