The Alteration Of NPAS4-BDNF In Neuropathic Pain Associated With Depression And The Potencial Intervention

Objective:Neuropathic pain(NPP),defined as a pain syndrome following the lesion or disease affecting the somatosensory system,with the morbidity up to 23.2%,attracts more and more attention from clinicians and basic research scholars.The NPP often results in some neuropsychological disorders including anxiety,cognitive dysfunction,and depression.Epidemiological studies have shown that depression occurs in 50%of patients with NPP,leading to the increased therapeutic complexity,the deteriorated quality of life,and the aggravated cost of life.Currently,the majority of mechanisms underlying the process of NPP induing depression include enhancement in central inflammation,dysfunction of monoamonergic system,reduction in neurogenesis,and impairment in synaptic plasticity and so on.However,the exact mechanisms remain unclear yet.Neuronal PAS domain protein 4(NPAS4),an activity-dependent transcription factor,regulates the structure and function of plasticity in neurons,especially the synaptic connectivity between neurons.Brain derived neurotrophic factor(BDNF),which is regulated by some factors including NPAS4,plays a key role in the survival,differentiation,and synaptic plasticity of neurons.The synaptic plasticity in hippocampus is inpaired in the stress-induced depression;however the alteration of synaptic plasticity in the NPP-induced depression is still unknown.We hypothesized that the synaptic plasticity mediated by NPAS4-BDNF is involved in the NPP-induced depression.Therefore,the purposes of this study are to investige:(1)wether NPP may result in depression-like behaviors in rats;(2)the alteration of hippocampal NPAS4 and BDNF in the NPP-induced depression rats;(3)the alteration of hippocampal synaptic plasticity in the NPP-induced depression rats;and(4)the alteration of behaviors and hippocampal NPAS4,BDNF,and synaptic plasticity after the intervention of enriched environment(EE)or ketamine.Method:Spared nerve injury(SNI)was used to establish the NPP model.Male Sprague-Dawley(SD)rats were randomized equally divided into 5 groups:Sham group,SNI group,SNI+EE group,SNI+saline group,and SNI+ketamine group.The mechanical and thermal pain thresholds were determined by paw withdrawl threshold(PWT)and paw withdraw lantency(PWL),respectively,on days 7,14,and 28 after surgry.The locomotor ability was determined by open filed test(OFT)on day 28 after surgery.The depression-like behaviors were determined by forced swimming test(FST)and scurose preference test(SPT)on day 28 after surgery.The hippocampal expressions of NPAS4 and BDNF were determined by Wertern blotting on day 28 after surgery.The density of dendritic spine in hippocampal CA1 zone was determined by golgi staining on day 28 after surgery.The local filed potential was determined by electrophysiological recording on day 28 after surgery.EE and ketamine were applied as interventions:(1)EE and stander environment were applied for the SNI+EE and SNI groups for 28 days,respectively.The PWT,PWL,locomotor activity,hippocampal expressions of NPAS4,BDNF,density of dendritic spine,and local filed potential in hippocampal CA1 zone were investigated on day 28 after surgery.(2)A dose of 20 mg/kg of ketamine and the same volume of saline were administrated in the SNI+ketamine and SNI+saline groups on day 28 after surgery,respectively.The PWT,PWL,locomotor activity,hippocampal expressions of NPAS4,BDNF,density of dendritic spine,and local filed potential in hippocampal CA1 zone were investigated at 0.5 h after ketamine administration.Results:(1)In the pain threshold test,compared with the sham group,the PWT and PWL were significantly decreased in the SNI group on days 7 d,14 d,28 d after surgery.Compared with the SNI group,the PWT and PWL had no significant difference in the SNI+EE group on day 28 after surgery.Compared with the SNI+saline group,the PWT,not the PWL,was significantly increased in the SNI+ketamine group at 0.5 h after ketamne administration.(2)In the OFT,there was no significant difference in the total distance,speed,center time,and corner time between the groups.(3)In the FST,compared with the sham group,the immobility time was significantly increased in the SNI group on day 28 after surgery.Compared with the SNI group,the immobility time was significantly reduced in the SNI+EE group on day 28 after surgery.Compared with the SNI+saline group,the immobility time was significantly decreased in the SNI+ketamine group at 0.5 h after ketamine administration.(4)In the SPT,there was no significant difference in the sucroce preference percent and total liquid consumed on day 28 after surgery at 0.5 h after ketamine administration between the groups.(5)In Western blotting test,compared with the sham group,the expressions of NPAS4 and BDNF were significantly decreased in the SNI group on day 28 after surgery.Compared with the SNI group,the expressions of NPAS4 and BDNF were significantly increased in the SNI+EE group on day 28 after surgery.Compared with the SNI+saline group,the expressions of NPAS4 and BDNF were significantly increased in the SNI+ketamine group at 0.5 h after ketamine administration.(6)In golgi staining,compared with the sham group,the density of dendritic spine in hippocampal CA1 zone was significantly decreased in the SNI group on day 28 after surgery.Compared with the SNI group,the density of dendritic spine in hippocampal CA1 zone was significantly increased in the SNI+EE group on day 28 after surgery.Compared with the SNI+saline group,the density of dendritic spine in hippocampal CA1 zone was significantly increased in the SNI+ketamine group at 0,5 h after ketamine administration.(7)In the local filed potential,the amplitude of evoked fEPSP in input-output curves had no significant difference among the groups.No significant difference was observed in paired-pulse facilitation among the groups.Compared with the sham group,the long term potential(LTP)in CA1 zone was impaired in the SNI group,which was rescued by EE in the SNI+EE group.Conclusion:(1)NPP may induce depression-like behaviors in rats.(2)The expressions of NPAS4 and BDNF are decreased in the rats with NPP-induced depression.(3)Hippocampal synaptic plasticity is impaired in the rats with NPP-induced depression.(4)Enriched environment and ketamine can effectively improve the aforementioned changes.In conclusion,decreased NPAS4-BDNF and impairment of synaptic plasticity are involved in in the NPP-induced depression.