ABSTRACT
Objective:To explore the effect of enriched environment on pain sensitivity, anxiety- and depressive-like behavior in selective nerve injury(SNI) rats model and its potential mechanism.Methods:A total of 36 male clean grade SD rats aged 6-8 weeks were randomly divided into three groups( n=12 in each group): sham operation+ standard environment group (sham group), SNI+ standard environment group (standard environment group), SNI+ enriched environment group (enriched environment group). The rat model of neuropathic pain was established by SNI.The rats in the enriched enviroment group were placed in an enriched enviroment 7 days before operation until 21 days after operation.The paw withdraw threshold(PWT) and paw withdraw latency (PWL) were performed to assess hyperalgesia.The open field test, elevated plus maze test, novelty suppressed feeding test and forced swimming test were used to assess anxiety and depression like behavior.The expressions of cAMP response element binding protein (CREB), p-CREB, brain-derived neurotrophic factor (BDNF), postsynaptic density-95 (PSD-95) and neuroligin 2 (NLGN2) were detected by Western blot.The expression of CREB and BDNF in contralateral ACC were measured by immunofluorescence.GraphPad prism 8.0 and SPSS 23.0 were used for data analysis.One way ANOVA was used for inter group comparison, repeated measurement ANOVA was used to analyze PWT and PWL results, and Tukey test was used for pairwise comparison. Results:(1) In PWT and PWL experiments, the interaction effect between group and time, group main effect and time main effect of PWT were significant ( F=13.4, 39.6, 369.6, all P<0.05), and the interaction effect between group and time, group main effect and time main effect of PWL were significant ( F=3.8, 10.3, 58.8, all P<0.05). Compared with sham group, PWT((8.0±3.5) g, (2.4±1.4) g, (2.3±1.1) g, (2.2±1.6) g, (1.6±0.5) g) and PWL((8.6±1.3) s, (7.3±1.5) s, (7.9±1.0) s, (6.6±1.1) s, (7.7±1.4) s) in standard environment group decreased at each time point (all P<0.05). (2) Compared with sham group, the number of entrying into the central area (1.3±1.7), the time of entrying into the central area((1.6±1.3) s), the proportion of entering open arms ((8.0±7.8) %) and the proportion of time in the open arms ((1.3±1.2) %) all significantly decreased in standard environment group ( t=4.585, 5.423, 4.682, 5.202, all P<0.05). The eating latency ((365.2±94.4) s) and immobility time ((127.6±24.3) s) dramatically increased ( t=6.008, 14.290, both P<0.05). The number and time of entrying into central area of enriched environment group were both higher than those of standard environment group(both P<0.05), while the eating latency and immobility time of enriched environment group were both lower than those of standard environment group(both P<0.05). (3) Compared with sham group(CREB: (1.6±0.2), (0.8±0.5); BDNF: (0.8±0.5), (1.0±0.4)), the expression of CREB ((1.8±0.1), (1.5±0.2)), BDNF ((0.9±0.6), (1.4±0.3)) in spinal cord and ACC of standard environment group increased (spinal: t=3.283, 4.989; ACC: t=5.502, 4.257, all P<0.05). The expression of PSD-95 ((1.6±0.2), (1.0±0.2) and NLGN2 ((1.5±0.5), (1.1±0.2)) also increased in ACC of standard enviroment group ( t=4.257, 2.214, both P<0.05). Compared with standard environment group, the expression of CREB (1.3±0.3), BDNF (0.7±0.4), PSD-95(1.0±0.3) and NLGN2(1.1±0.4) in spinal cord of enriched environment group decreased ( t=5.007, 2.166, 2.358, 2.322, all P<0.05). The expression of PSD-95(1.2±0.3) and NLGN2(1.1±0.2) also decreased in ACC of enriched environment group ( t=2.674, 2.944, both P<0.05). However, the expression of p-CREB (1.7±0.6) and BDNF (2.4±0.2) increased in ACC ( t=4.180, 7.610, P<0.05). Conclusion:Enriched environment can improve neuropathic pain and anxiety- and depressive-like behavior in SNI rats, which may be related to the change of synaptic plasticity in spinal cord and ACC.