ATP release from several sources is associated with tissue damage, neuronal and glial signaling (Salter et al., 1993,Tsuda et al., 2005). in rodent chronic pain models. Since up-regulation of chemokines and their receptors may be a mechanism that directly and/or indirectly contributes to the development and maintenance of chronic pain, these molecular molecules may represent novel targets for therapeutic intervention in sustained pain states. Keywords:Cathepsin S, Zidovudine CCR2, CX3CR1, Fractalkine, MCP-1, Neuropathy, Pain == 1. Introduction == Neuropathic pain is experienced in association with many types of injury to the nervous system or as a consequence of diabetes, cancer or infectious agents. From the therapeutic point of view, neuropathic pain often proves refractory to existing therapies. A better understanding of the cellular and molecular processes involved in the development of neuropathic pain is essential for the development of novel therapies. Many pathophysiological mechanisms underlie the development of neuropathic pain states. The site of these mechanisms include not only the damaged nerve and dorsal root ganglia (DRG), but also changes in the central processing of sensory information, most notably at the level of the spinal cord. This phenomenon has traditionally been considered a neuronally mediated Zidovudine response. Recent findings have highlighted the active involvement of glial cells in the pathogenesis of nerve injury-induced neuropathic pain and uncover new targets for potential analgesics (Watkins and Maier, 2003,Marchand et al., 2005,Tsuda et al., 2005,Scholz and Woolf, 2007). Microglia release a variety of mediators including pro-inflammatory cytokines and chemokines that contribute to pain signaling. Chemokines are small proteins that were initially characterized as chemotactic peptides controlling the trafficking of leukocytes (for review seeCharo and Ransohoff, 2006). Chemokine classification is based on the presence and position of the first cysteine residues. The CC group has two adjacent cysteines, the CXC group has one amino acid that separates the two cysteine residues, and the CX3X (three amino acids between two cysteines residues) chemokine CX3CL1 (also termed fractalkine) has only one member in its class. Chemokines are released locally from peripheral blood cells at Zidovudine sites of inflammation and Zidovudine are crucial during the inflammatory response since they are accountable for leukocyte recruitment to the site of damage. In addition, chemokines are also involved in pain processing as described in this chapter. == 1.1. Role of CCL2 in spinal nociceptive transmission == The understanding of the functional role of CCL2 in pain processing requires a precise knowledge of its distribution, and its co-localization with pain-related neuropeptides in DRG neurons and in their nerve terminals in Rabbit Polyclonal to OR10Z1 the dorsal horn of the spinal cord. Within DRG, CCL2 is constitutively expressed in small and medium diameter size neurons under nave conditions and in several chronic pain models (Fig. 1;Tanaka et al., 2004,White et al., 2005,Zhang and De Koninck, 2006). To identify the phenotype of CCL2-expressing cells, double-labeling immunohistochemistry combining CCL2 antibodies with classical neuronal markers revealed that CCL2-immunoreactivity was restricted to the cell bodies of DRG neurons. Among these, CCL2 labeling was detected in the subpopulation of peptidergic neurons immunoreactive for substance P and in primary sensory neurons expressing the neuropeptide CGRP (Dansereau et al., 2008). Moreover, CCL2-positive neurons also co-localized extensively with the capsaicin-heat and proton-gated ion channel, transient receptor potential vanilloid 1 (Dansereau et al., 2008). At higher magnification, confocal images of dually stained DRG neurons revealed that the intracellular pattern of staining for CCL2 only partially overlapped with those of substance P or CGRP (Fig. 1). Indeed, the neuropeptides substance P and CGRP were seen in punctate structures homogenously distributed throughout the cytoplasm whereas Zidovudine CCL2-ir formed large fluorescent puncta clustered around the nucleus within neuronal cell bodies (Dansereau et al., 2008). Confocal microscopy revealed the presence of CCL2 immunoreactivity in the dorsal horn of the spinal.