Pain Induces Postoperative Learning And Memory Impairment Via TNFα/CDK5/NR2B Signaling

[Objectives]Investigate if pain could induce cognitive dysfunction and the role of synapticNMDA receptors2B (NR2B) in this process.[Methods]1. Adult mice were separated into4groups: Sham (S); Incision (I)；Sham+EMLA (SE)；Incision+EMLA (IE). Left hind paw surgicalincisions were made under isoflurane anesthesia. Mechanical allodyniawas assessed using nylon von Frey filaments at3,7days after theincision. Learning and memory function was determined in the FearConditioning Test on days3,7and30after incision.2. Adult mice were separated into into2groups: Sham (S1); Incision(I1).Fear conditioning training took1day before incision, learning andmemory function was determined at days1,5after incision3. Adult mice were separated into4groups: Sham+Control (SC);Incision+Control (IC)；Sham+Roscovitine (SR)；Incision+Roscovitine (IR). Learning and memory function was determined by FearConditioning Test on days3,7after incision.4. Levels of synaptic, extrasynaptic, and total NR2B, TNFα and CDK5in the Cortex and Hipocampus were determined at3,7days after incisionby Western blot.5. Adult SD rats were separated into4groups: Saline; Complete Freundsadjunvant (CFA); CFA+Roscoviting;CFA+solvent.Thermal painthreshold was observed in one week after treatment, meanwhile,levels ofCDK5,p35-25, SYP and TrkB in the spinal cord dosal horn weredetermined by western blot.[Results]1. Open field test revealed no significant difference in the total traveldistance and mean speed between the incised mice (I) and the shamoperation (S). A dramatic decrease of Paw withdraw threshold (PWT)is observed in the mice at postoperative3days. EMLA rescues surgicalincision induced mechanical nociceptive threshold decrease.2. Surgical incision does not decrease freezing time in the context testof the Fear Conditioning Test (FCT) as compared to the sham group3days and7days post-operation. However, surgical incision decreasesfreezing time in the tone test of the FCT as compared to the sham group3days and7days post-operation. EMLA rescues learning and memory impairment induced by surgical incision. Roscovitine rescues surgicalincision induced learning and memory impairment at3,7post-operation.Surgical incision does not decrease freezing time in the context test andtone test of the FCT as compared to the sham group at30days post-operation. Post-training surgical incision does not decrease freezing timein the context test and tone test of the FCT as compared to the shamgroup1days and5days post-operation.3. Surgical incision significantly decreases level of synaptic NR2B andincrease CDK5and TNFα in the cortex at3days post-operation. EMLAtreatment inhibits the decrease of synaptic NR2B and the increase ofTNFα, CDK5in cortex induced by incision. Roscovitine treatmentinhibits the decrease of synaptic NR2B and increase of P35-P25in cortexinduced by incision.4. CDK5, P35-25in the spinal cord dorsal horn regulated thedevelopment of pain caused by CFA via SYP and TrkB pathway.[Conclusion]These results suggest that post-operative pain may contribute to learning andmemory impairment by decreasing the expression of synaptic NR2B in cortexof mice.