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To investigate whether meranzin hydrate (MH) can alleviate depression-like behavior and hypomotility similar to Chaihu Shugan Powder (CSP), and further explore the potential common mechanisms.Totally 120 Spraque-Dawley rats were randomly divided into 5-8 groups including sham, vehicle, fluoxetine (20 mg/kg), mosapride (10 mg/kg), CSP (30 g/kg), MH (9.18 mg/kg), [D-Lys3]-GHRP-6 (Dlys, 0.5 mg/kg), and MH+Dlys groups by a random number table, 8 rats in each group. And 32 mice were randomly divided into wild-type, MH (18 mg/kg), growth hormone secretagogue receptor-knockout (GHSR-KO), and GHSR+MH groups, 8 mice in each group. The forced swimming test (FST), open field test (OFT), tail suspension test (TST), gastric emptying (GE) test, and intestinal transit (IT) test were used to assess antidepressant and prokinetic (AP) effects after drug single administration for 30 min with absorbable identification in rats and mice, respectively. The protein expression levels of brain-derived neurotrophic factor (BDNF) and phosphorylated mammalian target of rapamycin (p-mTOR) in the hippocampus of rats were evaluated by Western blot. The differences in functional brain changes were determined via 7.0 T functional magnetic resonance imaging-blood oxygen level-dependent (fMRI-BOLD).MH treatment improved depression-like behavior (FST, OFT) and hypomotility (GE, IT) in the acute forced swimming (FS) rats (all P0.05), and the effects are similar to the parent formula CSP. The ghrelin antagonist [D-Lys3]-GHRP-6 inhibited the effect of MH on FST and GE (P0.05). Similarly, MH treatment also alleviated depression-like behavior (FST, TST) in the wild-type mice, however, no effects were found in the GHSR KO mice. Additionally, administration of MH significantly stimulated BDNF and p-mTOR protein expressions in the hippocampus (both P0.01), which were also prevented by [D-Lys3]-GHRP-6 (P0.01). Besides, 3 main BOLD foci following acute FS rats implicated activity in hippocampus-thalamus-basal ganglia (HTB) circuits. The [D-Lys3]-GHRP-6 synchronously inhibited BOLD HTB foci. As expected, prokinetic mosapride only had effects on the thalamus and basal ganglia, but not on the hippocampus. Within the HTB, the hippocampus is implicated in depression and FD.MH accounts for part of AP effects of parent formula CSP in acute FS rats, mainly via ghrelin-related shared regulation coupled to BOLD signals in brain areas. This novel functionally connection of HTB following acute stress, treatment, and regulation highlights anti-depression unified theory.

Several studies reported the relative antidepressant effects of Fructus Aurantii (FRA) with repeated treatment, the rapid antidepressant effects of FRA and the underlying mechanisms remained unclear. We, therefore, examined the rapid antidepressant actions of FRA in behavioral tests in mice and tested the underlying molecular mechanisms. We found FRA, like ketamine, reversed the behavioral deficits both in lipopolysaccharide(LPS)-induced and learned helplessness (LH) models at 1 day after a single administration. FRA was also capable of increasing the expressions of protein kinase A/cAMP-response element-binding protein/brain-derived neurotrophic factor (PKA/CREB/BDNF) signaling in hippocampus. Consistent with ketamine, FRA up-regulated the expressions of GABAergic receptor (GAD67) and glutamatergic receptor 1 (GluR1) in mouse hippocampus both exposed to LPS and LH. Moreover, synaptic proteins such as postsynaptic density-95 (PSD95) and synapsin1 were also up-regulated by a single dose of FRA both in LH and LPS models, like ketamine. Finally, metadoxine (an antagonist of CREB) inhibited the antidepressant effects of FRA in tail suspension test (TST) and forced swimming test (FST) in LPS-induced mice, which also blocked the phosphorylation of CREB and the expressions of neurotransmitters and synaptic molecules. Therefore, FRA had rapid antidepressant effects, which depended on PKA/CREB/BDNF pathway, subsequently regulated the downstream synaptic transmission.

Objective. Postincision pain often occurs after surgery and is an emergency to be treated in clinic. Electroacupuncture (EA) is a Chinese traditional treatment widely used to cure acute or chronic pain, but its mechanism is not clear. Interleukin-10 (IL-10) is a powerful anti-inflammatory cytokine that shows neuroprotective effects in inflammation and injury in the CNS. The present study attempts to reveal that IL-10 is crucial for EA analgesia on postincision pain. Methods. A model of incision pain was established in C57BL/6J mice. The pain threshold was detected by behavioral test, and the expression of IL-10 and its receptor was detected by an immunohistochemical method. C-fiber-evoked field potentials were recorded by in vivo analysis. Results. The mechanical allodynia induced by paw incision was significantly inhibited by pretreatment of EA in mice. Intrathecal injection of IL-10 neutralizing antibody (2 µg/10 µL) but not intraplantar injection (10 µg/10 µL) reversed the analgesia of EA. The upregulations of IL-10 mRNA and protein were induced by EA at 6 h and 1 d after incision, respectively. Spinal long-term potentiation (LTP), a substrate for central sensitization, was also suppressed by EA with IL-10. IL-10 recombinant protein (1 µg/10 µL, i.t.) mimicked the analgesia of EA on mechanical allodynia and inhibition on the spinal LTP. Posttreatment of EA after incision also transitorily relieved the mechanical allodynia, which can be blocked by spinal IL-10 antibody. IL-10 and its receptor, IL-10RA, are predominantly expressed in the superficial spinal astrocytes. Conclusions. These results suggested that pretreatment of EA effectively prevented postincision pain and IL-10 in spinal astrocytes was critical for the analgesia of EA and central sensitization.

Post-incision pain often occurs after surgery and is emergent to be treated in clinic. It hinders the rehabilitation of patients and easily leads to various types of postoperative complications. Acupuncture-combined anesthesia (ACA) is the combination of traditional acupuncture and modern anesthesia, which means acupuncture is applied at acupoints with general anesthesia. It was testified that ACA strengthened the analgesic effect and reduced the occurrence of postoperative pain, but its mechanism was not clear. Numerous reports have shown that chemokine receptor CX3CR1 is involved in the development and progression of many pathological pains. The present study was aimed to reveal whether ACA played the analgesic roles in the post-incision pain by affecting CX3CR1. A model of toe incision pain was established in C57BL/6J mice. The pain threshold was detected by behavioral test, and the expression of CX3CR1 protein was detected by immunohistochemical method and Western blot. The results showed that the significant mechanical allodynia and thermal hyperalgesia were induced by paw incision in the mice. Mechanical allodynia was significantly suppressed by ACA, but thermal hyperalgesia was not changed. CX3CR1 was mainly expressed in microglia in the spinal cord dorsal horn, and its protein level was significantly increased at 3 d after incision compared with that of naïve C57BL/6J mice. ACA did not affect CX3CR1 protein expression at 3 d after incision in the toe incision model mice. Paw withdrawal threshold was significantly increased at 3 d after incision in CX3CR1 knockout (KO) mice compared with that in the C57BL/6J mice. But the analgesic effect of ACA was disappeared in CX3CR1 KO mice. Accordingly, it was also blocked when neutralizing antibody of CX3CR1 was intrathecally injected (i.t.) 1 h before ACA in the C57BL/6J mice. These results suggest that CX3CR1 in microglia is involved in post-incision pain and analgesia of ACA.