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      Early Blockade of EphA4 Pathway Reduces Trigeminal Neuropathic Pain

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          Although the Eph receptor plays an important role in the development of neuropathic pain following nerve injury, there has been no evidence of the participation of the ephrin A4 receptor (EphA4) in the development of trigeminal neuropathic pain. The present study investigated the role of EphA4 in central nociceptive processing in rats with inferior alveolar nerve injury.

          Materials and Methods

          Male Sprague-Dawley rats were used in all our experiments. A rat model for trigeminal neuropathic pain was produced using malpositioned dental implants. The left mandibular second molar was extracted under anesthesia, followed by the placement of a miniature dental implant to injure the inferior alveolar nerve.


          Our current findings show that nerve injury induced by malpositioned dental implants evokes significant mechanical allodynia and up-regulation of EphA4 expression in the ipsilateral trigeminal subnucleus caudalis. Although daily treatment with EphA4-Fc, an EphA4 antagonist, did not produce prolonged anti-allodynic effects after the chronic neuropathic pain had been already established, an early treatment protocol with repeated EphA4-Fc administration significantly attenuated mechanical allodynia before initiation of chronic neuropathic pain. Finally, we confirmed the participation of the central EphA4 pathway in the development of trigeminal neuropathic pain by reducing EphA4 expression using EphA4 siRNA. This suppression of EphA4 produced significantly prolonged anti-allodynic effects.


          These results suggest that early blockade of central EphA4 signaling provides a new therapeutic target for the treatment of trigeminal neuropathic pain.

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          Most cited references 36

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          Eph receptor signalling casts a wide net on cell behaviour.

          Eph receptor tyrosine kinases mould the behaviour of many cell types by binding membrane-anchored ligands, ephrins, at sites of cell-cell contact. Eph signals affect both of the contacting cells and can produce diverse biological responses. New models explain how quantitative variations in the densities and signalling abilities of Eph receptors and ephrins could account for the different effects that are elicited on axon guidance, cell adhesion and cell migration during development, homeostasis and disease.
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            Chronic catheterization of the spinal subarachnoid space.

            To administer drugs into the spinal subarachnoid space of unanesthetized and intact rats and rabbits, a procedure is described whereby a polyethylene catheter (PE-10) may be inserted through a puncture of the atlanto-occipital membrane and secured to the skull. Calibration experiments carried out with bromophenol blue dye, 3H-naloxone and 14C-urea revealed first, that there was little rostro-caudal diffusion of the injectate along the spinal axis and secondly, that even for compounds such as naloxone which can rapidly permeate neural tissues, the levels which do appear in the brain are small following the spinal subarachnoid administration of the drug. Control injections, administered either acutely or repeatedly over a prolonged period of time, had no detectable effect on the animal's behavior. These observations, as well as the lack of pathology in the spinal cords of rats having such catheters for periods of up to 4 months suggests that the implant is well tolerated.
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              Bidirectional modulation of synaptic functions by Eph/ephrin signaling.

              Ephrin ligands and their cognate Eph receptors guide axons during neural development and regulate synapse formation and neuronal plasticity in the adult. Because ephrins are tethered to the plasma membrane and possess reverse signaling properties, the Eph-ephrin system can function in a bidirectional, contact-mediated fashion between two opposing cells. Eph receptors expressed on dendrites are activated by ephrins (on axons or on astrocytes) and regulate spine and synapse formation. They also participate in activity-induced long-term changes in synaptic strength such as long-term potentiation (LTP). When expressed on axon terminals, ephrins promote presynaptic differentiation and enhance neurotransmitter release, thereby supporting presynaptic forms of LTP. In some cases, Eph receptors can simply act as ligands for ephrins without any requirement for Eph receptor signaling, suggesting that the system does not always function bidirectionally.

                Author and article information

                J Pain Res
                J Pain Res
                Journal of Pain Research
                22 May 2020
                : 13
                : 1173-1183
                [1 ]Department of Oral Physiology, School of Dentistry, Kyungpook National University , Daegu, Korea
                Author notes
                Correspondence: Dong-Kuk Ahn Department of Oral Physiology, School of Dentistry, Kyungpook National University , 2177 Dalgubeol-daero, Chung-gu, Daegu41940, KoreaTel +82-53-660-6840Fax +82-53-421-4077 Email dkahn@knu.ac.kr

                These authors contributed equally to this work

                © 2020 Kim et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 5, References: 44, Pages: 11
                Original Research

                Anesthesiology & Pain management

                trigeminal, allodynia, sirna, epha4, ephrin, neuropathic pain


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