P2 receptors, microglial cytokines and chemokines, and neuropathic pain

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Injury to the nervous system as a consequence of bone compression in cancer, infection, autoimmune disease, trauma, and diabetes mellitus often causes debilitating chronic pain syndrome, termed neuropathic pain (Baron, 2006). Symptoms of neuropathic pain are spontaneous pain, hyperalgesia (the increased pain perception of noxious stimuli), and mechanical allodynia (pain hypersensitivity to normally innocuous stimuli). Neuropathic pain, especially allodynia, is often resistant to currently available drug treatments such as nonsteroidal anti‐inflammatory drugs and even opioids, but only when administered at doses that do not produce significant side effects (Woolf and Mannion, 1999; Scholz and Woolf, 2002). We are now beginning to understand that neuropathic pain is not just a symptom of disease but is a consequence of disordered functioning of the nervous system (Costigan et al., 2009; Beggs et al., 2012). Unraveling the mechanisms of pain hypersensitivity caused by nerve damage is therefore essential for the development of new therapeutic drugs for neuropathic pain.
Studies investigating how peripheral nerve damage develops neuropathic pain have indicated that molecular and cellular alterations in primary sensory neurons and in the spinal dorsal horn after peripheral nerve injury (PNI) have important roles in the pathogenesis of neuropathic pain (Woolf and Mannion, 1999; Woolf and Salter, 2000; Scholz and Woolf, 2002). Accumulating evidence from animal models of neuropathic pain indicates modification of neuronal networks in the spinal dorsal horn by PNI, which in turn leads to aberrant excitability in the dorsal horn (Woolf and Salter, 2000; Balasubramanyan et al., 2006; Braz et al., 2014; Prescott et al., 2014). These modifications include loss of function of inhibitory interneurons (cf. diminished activity of these cells or reduced effectiveness of the inhibitory neurotransmitters γ‐aminobutyric acid and glycine; Lu et al., 2013; Duan et al., 2014; Foster et al., 2015; Petitjean et al., 2015). Furthermore, another line of evidence has indicated that PNI‐induced hyperexcitability might be a consequence not of mere changes in neurons but rather of multiple alterations in glial cells such as microglia, the immune cells of the central nervous system (CNS; Watkins et al., 2001; Marchand et al., 2005; Tsuda et al., 2005; Scholz and Woolf, 2007; Suter et al., 2007; McMahon and Malcangio, 2009; Ji et al., 2014). This Review highlights recent advances in our understanding of the mechanisms that underlie neuropathic pain caused by PNI with a specific focus on purinergic signaling in spinal cord microglia.

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