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Neuropathic pain results from injury or disease causing dysfunction at any level of the somatosensory (primarily spinothalamic) system, including peripheral nociceptive axons, dorsal root ganglion (DRG), dorsal horn, spinothalamic pathway, and thalamus. The manifestations of neuropathic pain, including spontaneous pain, hyperalgesia, and thermal and mechanical allodynia, reflect excessive excitability of peripheral nociceptors (peripheral sensitization), central nociceptive neurons (central sensitization), or both. Sensitization reflects maladaptive plastic changes in the nociceptive system that result directly from axonal injury and from the effects of products of inflammation. There is abundant evidence that activation of microglia and astrocytes in the dorsal horn is common and constitutes an important amplification mechanism leading to neuropathic pain in the setting of peripheral nerve or spinal cord injury. Activated glial cells are also involved in sensitization of brainstem and thalamic neurons at a distance from the site of injury. The complex roles of the central glia and its mediators in the mechanisms of neuropathic pain have been extensively reviewed.1–9
NORMAL PAIN SIGNALING PAIN PROCESSING
The components of transmission of nociceptive information (“pain system”) include the nociceptive neurons of the DRG with unmyelinated C- and small myelinated Aδ axons that activate different types of neurons in the dorsal horn, particularly in lamina I and lamina V, which project via parallel pathways to the thalamus and to the brainstem. The primary DRG afferents also activate excitatory and inhibitory interneurons in lamina II that exert local control on nociceptive transmission.10–12 Similar organization occurs in the nociceptive trigeminal system. The nociceptive DRG neurons express different types of voltage-gated sodium (Na+) channels (particularly Nav1.7, Nav1.8, and Nav1.9), transient receptor potential (TRP) channels (including TRPV1 and TRPA), acid-sensitive channels, serotonin 5-HT3 receptors, and purinergic P2X receptors that are activated by noxious mechanical or chemical stimuli.11 In normal conditions, activation of Aδ and C-fiber nociceptors leads …
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