Lakhasly

relation between SCs and TN mainly involves two aspects.Increased Ca2th influx leads to increased release of the excitatory neurotransmitter, Glu, which activates NMDA and a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, leading to hyperalgesia and hypersensitivity.70 NGF expression is upregulated in injured SCs.Given the presence of CGRP receptors on SCs, prolonged exposure to CGRP, e.g. after nerve damage, increases release of IL-1b, 39 which induces hypersensitivity to pain and subsequently pathologic neuralgia SP is widely found in the peripheral nervous system and is an important molecule that mediates the production and conduction of pain; moreover, it plays an important role in neuropathic pain.43 Its biological function is mediated by the activation of three different neurokinin (NK) receptors, namely, NK1, NK2, and NK3, and has a preferential affinity for the NK1 receptor.44 Large amounts of SP can directly induce sensory neuron excitability, which leads to hyperalgesia.43 SP, which is the main messenger of harmful information, can be synthesized by TG cells and delivered to the trigeminal sensory nucleus and the peripheral head and face through central and peripheral synapses, respectively.45,46 Studies have reported that after nerve injury, SCs synthesize and release NGF, which can promote SP synthesis.47 Moreover, treatment with SP receptor blockers can alleviate TN caused by infraorbital nerve injury.43 As the upstream SP signal source, activated SCs release a series of neurotrophic factors, cytokines, and extracellular matrix, which can increase the local SP levels and cause TN. In summary, we present a pathway of the involvement of SCs in TN. After peripheral nerve injury, TNF-a expression increases;66 then, TNF-a binds to TNF-a receptors (TNFR) on the SCs and induces SCs to express the P2X4 receptor;67 P2X4 receptor is activated by ATP which is released by neurons and SCs to mediate Ca2th influx and increased BDNF release.68,69 BDNF binds with the trkB receptor that leads to KCC2 downregulation and NMDA receptor upregulation, which lays the foundation for pain production.SP activates the NK1 receptor, while CGRP inhibits SP degradation, leading to TN. Moreover, NGF can promote BDNF expression and thus cause TN.

relation between SCs and TN mainly involves two aspects. After trigeminal nerve injury, axons degenerate and demyelinate due to compression or inflammation.27 Activated SCs destroy the myelin sheath and engulf axon fragments and the detached myelin sheath, which leads to TN.28,29 Otherwise, activated SCs secrete molecules that induce hypersensitivity to pain, which leads to a decreased pain threshold that triggers TN.9
SCs are important factors in trigeminal nerve demyelination. Following nerve injury, SCs are activated and acquire the ability to differentiate and phagocytize.9,15 The activated SCs not only lose their original ability to maintain the myelin sheath but also begin to degrade and engulf it.20,35 Myelin degradation is generally considered to occur in two stages. During the early stage of injury, only SCs remove myelin.20 Subsequently, with the secretion of a large number of macrophage chemokines by SCs, macrophages join in the myelin removal. Myelin removal can reduce compression injury during nerve regeneration and eliminates potential myelin regeneration inhibitors.15 However, demyelination inevitably causes TN.36
As aforementioned, activated SCs regulate the expression of several molecules, including those associated with TN. In addition to the expression of pain-causing molecules, SCs can act as pain signal transducers by receiving pain signals, releasing the corresponding molecules, and participating in pain conduction
Calcitonin gene-related peptide (CGRP) is an important neuropeptide that is mainly found in the trigeminal ganglion (TG) and spinal dorsal root ganglion and is synthesized and released by sensory neurons.37 It promotes central excitability through inhibition of substance P (SP) degradation and prolongs SP-induced local neuroinflammation and pain in tissues. Further, CGRP can promote injured nerve repair.38,39 There have been recent reports of CGRP receptors on SCs in the peripheral nervous system.40 The fact that CGRP is an important neuralgia-causing substance suggests that SCs play an important role in TN pathogenesis and the nerve repair process. Studies have reported an upregulation of CGRP expression in the axon proximal to the nerve injury38; further, CGRP has been reported to reduce the pain threshold, which causes TN.41 Moreover, denervated SCs secrete matrix metalloproteinase, which leads to CGRP release and TN aggravation. Given the presence of CGRP receptors on SCs, prolonged exposure to CGRP, e.g. after nerve damage, increases release of IL-1b, 39 which induces hypersensitivity to pain and subsequently pathologic neuralgia
SP is widely found in the peripheral nervous system and is an important molecule that mediates the production and conduction of pain; moreover, it plays an important role in neuropathic pain.43 Its biological function is mediated by the activation of three different neurokinin (NK) receptors, namely, NK1, NK2, and NK3, and has a preferential affinity for the NK1 receptor.44 Large amounts of SP can directly induce sensory neuron excitability, which leads to hyperalgesia.43 SP, which is the main messenger of harmful information, can be synthesized by TG cells and delivered to the trigeminal sensory nucleus and the peripheral head and face through central and peripheral synapses, respectively.45,46 Studies have reported that after nerve injury, SCs synthesize and release NGF, which can promote SP synthesis.47 Moreover, treatment with SP receptor blockers can alleviate TN caused by infraorbital nerve injury.43 As the upstream SP signal source, activated SCs release a series of neurotrophic factors, cytokines, and extracellular matrix, which can increase the local SP levels and cause TN.
In summary, we present a pathway of the involvement of SCs in TN. After peripheral nerve injury, TNF-a expression increases;66 then, TNF-a binds to TNF-a receptors (TNFR) on the SCs and induces SCs to express the P2X4 receptor;67 P2X4 receptor is activated by ATP which is released by neurons and SCs to mediate Ca2þ influx and increased BDNF release.68,69 BDNF binds with the trkB receptor that leads to KCC2 downregulation and NMDA receptor upregulation, which lays the foundation for pain production. Increased Ca2þ influx leads to increased release of the excitatory neurotransmitter, Glu, which activates NMDA and a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, leading to hyperalgesia and hypersensitivity.70 NGF expression is upregulated in injured SCs. NGF activation of the trkA receptor can lead to the upregulation of the SP, CGRP, and TRPV1 receptors. SP activates the NK1 receptor, while CGRP inhibits SP degradation, leading to TN. Moreover, NGF can promote BDNF expression and thus cause TN.