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Neuropathic Pain Signaling In Dorsal Horn Neurons

Neuropathic pain arises from an injury discharge originating at the site of nerve injury, as well as from the development of ectopic impulses in the injured nerve. Many patients suffer from neuropathic pain due to injury to the peripheral nervous system (including dorsal root ganglia and dorsal roots) or the CNS. These injuries may result from surgery, diabetic neuropathy, amputation, viral infection, trauma, stroke, and other causes. Hyperexcitability develops in the CNS dorsal horn neurons, and both peripheral and spinal elements contribute to neuropathic pain, so that spontaneous pain occurs or normally innocuous stimuli produce pain. Inflammatory mediators and aberrant neuronal activity activate several signaling pathways in postsynaptic dorsal horn neurons that mediate the induction and maintenance of neuropathic pain through both post-translational and transcriptional mechanisms...

Neuropathic Pain Signaling In Dorsal Horn Neurons

Pathway Summary

Neuropathic pain arises from an injury discharge originating at the site of nerve injury, as well as from the development of ectopic impulses in the injured nerve. Many patients suffer from neuropathic pain due to injury to the peripheral nervous system (including dorsal root ganglia and dorsal roots) or the CNS. These injuries may result from surgery, diabetic neuropathy, amputation, viral infection, trauma, stroke, and other causes. Hyperexcitability develops in the CNS dorsal horn neurons, and both peripheral and spinal elements contribute to neuropathic pain, so that spontaneous pain occurs or normally innocuous stimuli produce pain. Inflammatory mediators and aberrant neuronal activity activate several signaling pathways in postsynaptic dorsal horn neurons that mediate the induction and maintenance of neuropathic pain through both post-translational and transcriptional mechanisms.Peripheral nerve injury induces release of the neurotransmitter glutamate and the neuromodulators Tachykinin 1 (Tac1) and brain-derived neurotrophic factor (BDNF) from the central terminals of primary afferents. Glutamate is the major excitatory neurotransmitter in the spinal cord and it acts on ionotropic glutamate receptors AMPA, and N-methyl D-aspartate receptors (NMDAR), as well as metabotropic glutamate receptors (MGLURs). Whereas AMPA receptors are important for the rapid excitatory synaptic transmission of physiological nociception, NMDARs play a critical role in plasticity in the CNS. Activation of NMDARs and Ca2+ permeable AMPA receptors in the spinal cord leads to Ca2+ influx. Stimulation of MGLURs and NK1Rs results in PLC-mediated production of IP3, which stimulates Ca2+ release from intracellular stores. The increase in intracellular Ca2+ activates CamK and PKC. BDNF released from presynaptic terminals also act on postsynaptic TRKB receptors in dorsal horn neurons, which increases the activity of NMDARs through tyrosine phosphorylation of Src; thus, contributing to the induction of neuropathic pain. PKC, CamK and Src all increase the activity of NMDARs. Activation of ERKs by TRKB, PKA, PKC and PI3K, an activation that involves NMDARs, AMPA receptors, and MGLURs, can suppress the activity of potassium channel KCND2, which generally suppresses excitability of the neuron. CamK positively regulates the activity of NMDARs and AMPA receptors. These posttranslational steps result in an overall increased sensitivity of dorsal horn neuron to afferent input, contributing to the generation of central sensitization. The activation of ERKs, PKA, and CamK activates the transcription factors CREB, Elk1, and c-Fos, leading to increased transcription of prodynorphin, Tac1, nNOS, COX2, SCn, α2δ Ca2+ Channel (CaCn) subunit, and TRKB. The protein or peptide products of these genes act together to maintain heightened excitability and synaptic responsiveness, and thus promote central sensitization and neuropathic pain.The most distinctive symptom of neuropathic pain is mechanical allodynia, which is painful responses to normally innocuous tactile stimuli. Neuropathic pain is also often characterized by hyperalgesia, which is increased responsiveness to noxious stimuli, as well as mechanical and thermal stimuli. Currently available drugs provide relief of neuropathic pain in only a fraction of patients, sometimes of enduring quality but often lasting no longer than the drug's presence at the site. ERK activation in dorsal horn neuron is nociceptive-specific and can be suppressed by several analgesics. Development of specific inhibitors for ERKs may lead to new therapies for neuropathic pain.

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