Nerve injury, trauma, and/or infection evoke a cascade of cellular events in the PNS, including a neuroin-flammatory response with the release of chemical mediators, including many proinflammatory cytokines and chemokines.86,87 Cytokines and chemokines (small che-moattractant cytokines) are growth factor proteins secreted primarily from leukocytes as part of the immune and inflammatory response88 and have been demonstrated to play a role in the pathogenesis of pain.87 These factors can act on neurons to induce changes in gene expression, which in turn lead to the emergence of abnormal electrical activity, known to be essential for the manifestation of neuropathic pain behavior. Following nerve trauma, tumor necrosis factor-a (TNFa) is released from Schwann cells and infiltrating and resident macrophages, and in turn stimulates the sequential production and release of interleukin-1 p (IL-1p) and interleukin-6 (IL-6) (Figure 1.6).86 Accordingly, neutralizing antibodies to TNFa and IL-1p reduce behavioral signs of experimental neuropathic pain90,91 and IL-6 knockout mice fail to exhibit neuropathic pain after nerve injury.92
Intact and injured sensory neurons are known to express receptors which respond to TNFa, IL-1p, and IL-6. However, the direct mechanism of neuronal sensitiza-tion remains to be fully determined. Indirect evidence suggests an action of TNFa on neuronal sodium or calcium channels,93 whereas IL-1p may be involved in a complex signaling cascade that leads to the production of pronociceptive compounds (such as nitric oxide, NGF, and prostaglandins) from immune cells or Schwann cells. Such substances lead to changes in gene expression and neuronal excitability in intact nociceptors.94 The gp130 cytokines, IL-6 and leukemia inhibitory factor (LIF), have been shown to be crucial in the up-regulation of key modulators of sensory processing, such as brain-derived neurotrophic factor (BDNF), galanin, and substance P following nerve injury.94 The chemokine CCL2 (MCP-1) is another injury-induced factor that accumulates within sensory neurons in models of neuropathic pain22 and contributes to macrophage recruitment. CCL2 has been implicated in the maintenance of neuropathic pain and knockout mice for the receptor, CCR2, fail to develop signs of neuropathic pain.95 Recent developments in the understanding of the importance of nonneuronal cells and inflammatory mediators in the response to damage of the peripheral nervous system has greatly aided the understanding of peripheral mechanisms of neuropathic pain.
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