Neuropathic pain is a class of pain caused by an injury or diseases of the somatosensory system and characterized by spontaneous pain,allodynia,and hyperalgesia.It is well established that central sensitization is one of the key mechanisms underlying the development and maintenance of neuropathic pain.Cannabinoid receptor 1 (CB1R) of endocannabinoid system modulates synaptic transmission,regulates synaptic plasticity,inhibits central sensitization,and thus attenuates neuropathic pain.Recent studies have shown that activation of CB1R also involves in the relief of neuropathic pain-induced depression.

Depression is a common mental disease, which mainly presents with a state of low mood and aversion to activity. Epigenetics is to study the influence of structural modification of pre?transcriptional gene to gene function in chromatin level. Recent studies have found that epigenetic mechanisms including DNA methylation, histone modification, and non?coding RNA regulation play important roles in the pathogenesis of depression. This article reviews the research advances on epigenetic mechanisms of depression.

Depression is a common mental disease, which is the leading cause of suicide.Ketamine, a commonly used gener-al anesthetic in clinical practice, exerts a rapid and effective antidepressant effect, and reduces suicide ideation in patients with treat-ment-resistant depression quickly.Brain-derived neurotrophic factor ( BDNF) is a neurotrophic factor widely expressed in central nerv-ous system, the increase of which has been shown to be critical in the antidepressant effect of ketamine.This article aims to review the role of BDNF and its downstream signaling pathways in the antidepressant effect of ketamine.

Objective Accumulating evidence has demonstrated that the sub-anesthetic dose of ketamine exerts rapid and ro-bust antidepressant-like effects though its action mechanisms are not yet fully understood .The aim of this study was to investigate the role of gamma-aminobutyric acid ( GABA) in the antidepressant effects of ketamine . Methods Thirty-two male Wistar rats were e-qually randomized into four groups: saline, ketamine, GABA, and GABA+ketamine.All the animals were implanted with a guide cannula into the lateral ventricle and on the eighth day after operation subjected to a 15 min forced swimming test (FST) for the estab-lishment of a depression model .At 24 h after modeling , the rats of the saline and ketamine groups were treated intracerebroventricularly with 2μL isotonic saline solution, and those of the GABA and GABA +ketamine groups with 50μg (2μL) GABA, followed by intrap-eritoneal administration of 1 mL saline in the former two groups and 10 mg/kg (1 mL) ketamine in the latter two groups 10 min later.At 30 min after treatment , the open field test ( OFT) was carried out for crossing and rearing scores and a 6-min FST was performed to re-cord the immobility time in the last 5 minutes.The content of GABA in the prefrontal cortex of the rats was measured following behav -ioral tests. Results The immobility time was significantly decreased in the ketamine group ([107.5 ±21.2]sec) as compared with the saline, GABA, and GABA+ketamine groups ([167.2 ±22.1], [159.8 ±17.5], and [143.8 ±22.1]sec) (P<0.05), with no significant difference between the GABA and GABA +ketamine groups (P>0.05).The level of GABA in the prefrontal cortex was remarkably lower in the ketamine group ([12.4 ±3.4]ng/mg prot) than in the saline, GABA, and GABA+ketamine groups ([23.3 ± 6.3], [27.3 ±5.7], and [18.0 ±5.4]ng/mg prot) (P<0.05), but markedly higher in the GABA than in the GABA +ketamine group (P<0.05).OFT scores exhibited no significant difference in the lo-comotor activity among the four groups of rats ( P >0.05 ). Conclusion The antidepressant effects of ketamine are related to the decreased GABA level in the prefrontal cortex in rats receiving FST .

Objective To observe the variation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and microglia in the comorbidity of neuropathic pain and depression and discuss the related mechanism.Methods The spared nerve injury model was used.Forty-four male adult Sprague Dawley rats were randomly divided into the following four groups (n=11 each): sham+vehicle group (group SV), sham+APO group (group SA), SNI+vehicle group (group SNV), SNI+APO group (group SNA).In groups SA and SNA, rats were intraperitoneally injected with apocynin (APO) 15 mg/kg 24 hours and 1 hour before SNI and continued once daily until the 14th day.The rats in the other two groups received the equal volume of vehicle.The mechanical withdrawal threshold (MWT) was tested 1 day before SNI and 7 days and 14 days after SNI, and the open field test, the forced swimming test and the sucrose preference test were performed 14 days after SNI.The prefrontal cortex were collected 2 hour after the behavior tests.The expression of gp91phox was detected by Western blot and the expression of Iba1 and gp91phox were detected by double-immunofluorescance staining.Results The reduced MWT, the increased immobility time, the decreased sucrose consumption and the increased content of gp91phox were observed in group SNV compared with groups SV, SA and SNA (P<0.05).The expression of Iba1 and gp91phox were increased in group SNV.The total travel distance in the open field test and the total liquid consumption in the sucrose preference test had no significant difference among the four groups.Conclusion Neuropathic pain may induce depressive behaviors and activate NADPH oxidase in the prefrontal cortex.Moreover, the inhibition of NADPH oxidase by APO can alleviate neuropathic pain and depression, which is potentially related to the activation of microglia.

Objective To investigate the effects of different doses of ketamine on brain-derived neurotrophic factor (BDNF) and tyrosine receptor Idnase B (TrkB) in the hippocampus in mentally depressed rats.Methods Fifty male Wistar rats weighing 180-220 g were randomly divided into 5 groups ( n = 10 each): group control (group C) and groups K1-4 ketamine 2.5, 5.0, 10.0 and 20.0 mg/kg. On the 1st day the animals were forced to swim for 15 min. On the 2nd day ketamine 2.5, 5.0, 10.0 and 20.0 mg/kg were given iniraperitoneally in groups K1-4 respectively at 30 min after administration. The immobility time of the rats during the forced swimming test was recorded. The animals were then decapitated. The hippocampus was harvested for determination of BDNF and TrkB levels. Results Ketamine significantly decreased the immobility time during forced swimming test in a dose-dependent manner. The BDNF and TrkB levels in the hippocampus were significantly increased in K, and K4 groups as compared with group C, and K1 and K2 groups. Conclusion The increased levels of BDNF and TrkB in the hippocampus are involved in the dose-dependent antidepressant effect of ketamine.

ObjectiveTo study the role of L-arginine/nitric oxide (NO) pathway in the antidepressant effects of ketamine.MethodsForty two male Wistar rats (200-250 g) were equally randomized into 7 groups ( n =6 ):control group ( C group ),L-Arginine ( a precursor of NO ) group ( LA group),L-NAME ( an non-selectivity inhibitor of NO synthase) group ( LN group),ketamine 3 mg/kg group ( K3 group),ketamine 10 mg/kg group (K10 group),L-Arginine + ketamine 10 mg/kg group(LAK10 group),L-NAME + ketamine 3 mg/kg group (LNK3 group).The forced swimming test (FST) of 15 min (pre-test session) was used to establish a rat depression model,then twenty-four hours later FST (test session) was carried out of 6 min and the immobility time in last 5 min was recorded. All the groups were pretreated with saline 1.0 ml,L-arginine 750 mg/kg or L-NAME 30 mg/kg 90 min before FST.Saline 1.0 ml,ketamine 3.0 mg/kg or ketamine 10.0 mg/kg were injected 60 min before FST.The content of hippocampal NO was detected immediately after ethology measurement.ResultsCompared with C group (immobility time:( 139.0 ± 27.6)s),the immobility time decreased significantly (( 85.5 ± 34.2),(91.3 ±31.6)s) in K10 group and LNK3 group (P＜0.05),K3 group,LA group,LAK10 group and LN group had no significant difference (P＞0.05) ;compared with C group ( (0.61 ±0.21 ) μmol/gProt),the content of NO increased in LA group ( ( 1.09 ±0.39) μmol/gProt) and decreased in K10 group and LNK3 group significantly( (0.28 ± 0.12),(0.31 ± 0.14 ) μmol/gProt) (P ＜ 0.05 ),K3 group,LAK10 group and LN group had no significant difference (P ＞ 0.05).ConclusionThe antidepressant effects of ketamine are related to the suppression of L-arginine/nitric oxide pathway.

Objective To observe the effects of ketamine on the behavior and indoleamine 2,3-dioxygenase (IDO ) signaling pathway in the rats with pain and depression comorbidity. Methods Twenty-four male adult SD rats,aged 2 months,weighing 200-250 g,were randomized into three groups:control group (group S),saline group (group N)and ketamine group (group K), eight in each group.CFA (50 μl)was injected into the right tibiotarsal joint cavity to establish the model of pain and depression comorbidity in the groups N and K,whereas saline (50 μl)was injected in the group S.The mechanical withdrawal threshold (MWT)and the immobility time were measured 1,7,and 14 days after the CFA injection.After the behavioral tests 14 days after the CFA injection, saline (1 ml)was intraperitoneal administrated in the group N and ketamine 20 mg/kg (1 ml)was in-traperitoneal administrated in the group K 14 days after CFA injection.The MWT and immobility time were measured 1 h after administration in the three groups to evaluate the behavioral changes. Then,the hippocampus,prefrontal cortex,cingulated gyrus and plasma were harvested to determine the levels of IL-6 and IDO using an enzyme-linked immunosorbent assay after the behavioral tests. Results Compared with the group S,the MWT was decreased and the immobility time was signifi-cantly increased in the group N and group K (P <0.05).Compared with the group N,the MWT was increased (P <0.05),the immobility time was decreased (P <0.05),and the levels of IL-6 and IDO in the hippocampus,prefrontal cortex and cingulated gyrus were significantly decreased in the group K (P < 0.05 ).Conclusion Ketamine can effectively treat pain and depression comorbidity,which may be attributed to the inhibition of IDO signaling pathway in different brain regions of rats.

Depression is one of the major types of psychiatric disorders, and often accompanies hyperalgesia except for mood alteration. At present, the mechanism of depression related hyperalgesia is mainly focused on monoamines, inflammatory cytokines, brain-derived neurotrophic factors and related neural circuits. At present, there is still a lack of specific treatment drugs for depression related hyperalgesia; and psychological therapy and traditional Chinese medicine therapy can play active auxiliary roles. In this review, the latest research progress of the above contents are noted to provide references for research and prevention of this disease.

Depression is one of the major types of psychiatric disorders, and often accompanies hyperalgesia except for mood alteration. At present, the mechanism of depression related hyperalgesia is mainly focused on monoamines, inflammatory cytokines, brain-derived neurotrophic factors and related neural circuits. At present, there is still a lack of specific treatment drugs for depression related hyperalgesia; and psychological therapy and traditional Chinese medicine therapy can play active auxiliary roles. In this review, the latest research progress of the above contents are noted to provide references for research and prevention of this disease.