Notch Signaling Pathway Plays A Pivotal Role In The Development Of Neuropathic Pain

Background: Pain is the most challenging research lies in both medicine andbiology, which arises many problems such as psychological problems, physicalproblems and social problems. More and more people pay attention to it. The painarising as a direct consequence of a lesion or disease affecting the somato-sensorysystem is defined as neuropathic pain, which is one of the most tricky chronic pain.So far, the pathogenesis of neuropathic pain is not well known, and is lacked ofefficient treatment.Comparing with physical pain, initiation and propagation of neuropathic pain,the process is very complex. Nervous system structure and function plasticitychange is the basic of neuropathic pain. Mean the while, The Notch signalingpathway has been proved to be involved in the development of nervous system.Recent studies showed that Notch receptors and ligands can also express in thenervous system in adult animals. However, whether Notch signaling pathway has afunction in adult was not fully understood. The present study was designed toinvestigate the function of Notch signaling pathway in nociceptive tranmision,especially in neuropathic pain in adult rats. Experiment1Effects of DAPT by the intrathecal administration onpain behavior in neuropathic pain ratsObjective: To investigate the key enzyme of the Notch signaling pathway—agamma-secretase inhibitor DAPT influenced on pain behavior in neuropathic painrats.Methods: Copying neuropathic pain models, including SNI and CCI. Ⅰ toobserve effects of i.t. DAPT before surgery on mechanical hyperalgesia in SNI rats:A total of30male SD rats were randomly assigned to three groups: Sham group,only exposure sciatic never without injury; SNI+DAPT (i.t.30min before injury);SNI+DMSO (i.t.30min before injury); Ⅱ to observe effects of i.t. DAPT3daysafter injury on mechanical hyperalgesia in SNI rats: A total of20male SD ratswere randomly assigned to two groups: SNI+DAPT (i.t3d after injury);SNI+DMSO (i.t3d after injury). Ⅲ to observe effects of i.t. DAPT beforesurgery on mechanical hyperalgesia and thermal hyperlgesia in CCI rats.A total of30male SD rats were randomly assigned to three groups: sham group, onlyexposure sciatic never without injury; CCI+DAPT (i.t.30min before injury);CCI+DMSO (i.t.30min before injury); Ⅳ to observe effects of different doses ofDAPT on mechanical hyperalgesia in SNI rats: A total of50male SD rats wererandomly assigned to five groups: control group, SNI group, SNI+DAPT5、15、50and150g group. And the change of mechanical withdrawal threshold andthermal withdrawal latency to be observed before and after administrationrespectively.Results: Ⅰ.Comparing with that of DMSO group, the MWT of SNI rats could be enhanced significantly by i.t.50g DAPT30min before nerve injury, and it couldlast for more than21days, prompting that DAPT can inhibit the occurrence ofneuropathic pain. Ⅱ. i.t50g DAPT after3d nerve injury could transverse thereduction of MWT in SNI rats, but the maintenance of this fuction could not bemore than48hours, and i.t DAPT repeatedly once a day for one week had asimilar function, prompting that DAPT had a―cover effect‖. Ⅲ DAPT not onlyprevented the reduction of MWT in CCI rats, but also enhanced the TWL in CCIrats. Ⅳ DAPT played analgesic role in SNI rats in a dose-dependent manner.Conclusion: DAPT had a distinctly analgesic function in a dose-dependentmanner in different neuropathic pain rats.Experiment2The Notch signaling expressed in nociceptiveinformation transmission pathwayObjective: To investigate the change of the Notch signaling in nociceptiveinformation transmission pathway after nerve injury, to understand the relationshipbetween Notch signaling pathway and neuropathic pain.Methods: The SNI model was only used in this part. The sciatic nerve, L4-5DRGand L4-5spinal cord segments were cut before surgery and3d,7d and14d aftersurgery. And then the Notch signaling pathway molecules express were assessedby immunofluorescence, western blotting and Real-time PCR.Results: Ⅰ. NICD is expressed in the sciatic never of adults rat, and has asignificant up-regulation after nerve injury （P<0.05）. Ⅱ. NICD is expressedmainly in the pepitide neurons in DRG, and increases significantly after nerveinjury（P<0.05）.Ⅲ. NICD is expressed in the dorsal horn of spinal cord, andincreases after nerve injury. Conclusion: Activation of the Notch signaling pathway may contribute to thegeneration and development of neuropathic pain. The upregulation of NICD in thespinal cord and DRG after nerve injury is an important factor for the developmentof neuropathic pain, and inhibition of-secretase may be a potential therapeuticstrategy for treating neuropathic pain.