Blood-nerve barrier enhances chronic postsurgical pain via the HIF-1α/ aquaporin-1 signaling axis.

BACKGROUND: Blood nerve barrier (BNB) participates in the development of neuropathic pain. AQP1 is involved in peripheral pain perception and is negatively correlated with HIF-1α phenotype, which regulates endothelial permeability. However, the role of HIF-1α-AQP1-mediated BNB dysfunction in Chronic Postsurgical Pain (CPSP) has not been reported. METHODS: Male Sprague-Dawley rats were randomized into 5 groups: (i) Naive group; (ii) Sham group; (iii) SMIR group: skin/muscle incision and retraction for one hour. Behavioral tests were performed for the three groups, BNB vascular permeability and western blotting were conducted to determine HIF-1α and AQP1 protein expression. (iv) The SMIR + HIF-1α inhibitor group; (v) SMIR + DMSO group. Rats in the two groups were administered with HIF-1α inhibitor (2ME2) or DMSO intraperitoneally on the third day post-SMIR surgery followed by performance of behavioral tests, BNB permeability assessment, and determination of HIF-1α, AQP1 and NF200 protein levels. RESULTS: The permeability of BNB was significantly increased and the expression of AQP1 was downregulated on the 3rd and 7th days post-operation. AQP1 is mainly located in neurons and NF200, CGRP-positive nerve fibers. HIF-1α was highly expressed on the third day post-operation. HIF-1α inhibitor reversed the decrease in AQP1 expression and increase in NF200 expression, barrier permeability and hyperalgesia induced by SMIR on the 3rd day post-surgery. CONCLUSIONS: Early dysfunction of BNB mediated by HIF-1α/AQP1 activated by SMIR may be an important mechanism to promote acute postoperative painful transformation of CPSP. Preadaptive protection of endothelial cells around nerve substructures may be an important countermeasure to inhibit CPSP transformation. Early impairment of BNB function mediated by HIF-1α/AQP1 activated by SMIR may be an important mechanism for promoting acute postoperative pain transformation of CPSP.

Z-Guggulsterone Produces Antidepressant-Like Effects in Mice through Activation of the BDNF Signaling Pathway.

Background: Z-guggulsterone, an active compound extracted from the gum resin of the tree Commiphora mukul, has been shown to improve animal memory deficits via activating the brain-derived neurotrophic factor signaling pathway. Here, we investigated the antidepressant-like effect of Z-guggulsterone in a chronic unpredictable stress mouse model of depression. Methods: The effects of Z-guggulsterone were assessed in mice with the tail suspension test and forced swimming test. Z-guggulsterone was also investigated in the chronic unpredictable stress model of depression with fluoxetine as the positive control. Changes in hippocampal neurogenesis as well as the brain-derived neurotrophic factor signaling pathway after chronic unpredictable stress/Z-guggulsterone treatment were investigated. The tryptophan hydroxylase inhibitor and the tyrosine kinase B inhibitor were also used to explore the antidepressant-like mechanisms of Z-guggulsterone. Results: Z-guggulsterone (10, 30 mg/kg) administration protected the mice against the chronic unpredictable stress-induced increases in the immobile time in the tail suspension test and forced swimming test and also reversed the reduction in sucrose intake in sucrose preference experiment. Z-guggulsterone (10, 30 mg/kg) administration prevented the reductions in brain-derived neurotrophic factor protein expression levels as well as the phosphorylation levels of cAMP response element binding protein, extracellular signal-regulated kinase 1/2, and protein kinase B in the hippocampus and cortex induced by chronic unpredictable stress. Z-guggulsterone (10, 30 mg/kg) treatment also improved hippocampal neurogenesis in chronic unpredictable stress-treated mice. Blockade of the brain-derived neurotrophic factor signal, but not the monoaminergic system, attenuated the antidepressant-like effects of Z-guggulsterone. Conclusions: Z-guggulsterone exhibits antidepressant activity via activation of the brain-derived neurotrophic factor signaling pathway and upregulation of hippocampal neurogenesis.

Role of caveolin-1 in chronic postsurgical pain in rats.

Chronic postsurgical pain (CPSP) has a high incidence, but the underlying mechanisms remain elusive. Previous studies have indicated that caveolin-1 (Cav-1) plays a notable role in pain modulation. To study the role of Cav-1 in CPSP in the present study, a rat model of skin/muscle incision and retraction (SMIR) was established. Under anesthesia, skin and superficial muscle of the medial thigh were incised and a small pair of retractors inserted. It was revealed that SMIR increased the expression of Cav-1 in the dorsal root ganglion (DRG) and the injured tissue around the incision. Furthermore, the infiltration of endothelial cells and macrophages in the injured tissue around the incision increased constantly, and the vascular permeability increased due to the destruction of the vascular endothelial barrier function around the injured tissue. Cav-1 was mainly expressed by CD68-positive macrophages and CD34-positive endothelial cells in the injured tissues around the incision, while it was also primarily localized in the medium and large neurofilament 200-positive neurons and a small number of calcitonin gene-related peptide- and isolectin B4-positive small and medium-sized neurons in the DRG. The results demonstrated that the sustained high expression levels of Cav-1 in the injured tissue around the incision could lead to the dysfunction of the vascular endothelial barrier and, thus, could induce the inflammatory response through the lipoprotein transport of endothelial cells, thereby resulting in peripheral sensitization. In addition, the sustained high expression levels of Cav-1 in the DRG could sensitize large-sized neurons and change the transmission mode of noxious stimuli. The findings of the present study indicated that a Cav-1-mediated process could participate in neuronal transmission pathways associated with pain modulation.

Cannabinoid receptor agonist WIN55212-2 reduces unpredictable mild stress-induced depressive behavior of rats.

BACKGROUND: Depression is a neurological disorder characterized by persistent low mood. A number of studies have suggested that the use of type 1 cannabinoid receptor (CB1R) agonists can reduce depressive behavior, but its effect on the depressive behavior and nerve damage of rats exposed to chronic unpredictable mild stress (CUMS) has not been reported. METHODS: Rats were exposed to CUMS for 4 weeks to induce depressive behavior. Male Sprague-Dawley (SD) rats aged 6-8 weeks were randomly divided into six groups: control group (control), depression group (CUMS), depression + fluoxetine group (Flu), depression + WIN55212-2 group (WIN), depression + NF-κB inhibitor group (PDTC), and depression + WIN + PDTC group (WIN + PDTC). We performed four behavioral experiments test to evaluate the depressive behaviors of rats. Hematoxylin and eosin (HE) and Nissl staining were performed to observe the neuron structures of the hippocampus. Enzyme-linked immunosorbent assay (ELISA) was used to measure the concentrations of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and cyclooxygenase-2 (COX-2). Biochemical experiments were performed to evaluate the concentrations of nitric oxide (NO), malondialdehyde (MDA), reactive oxygen species (ROS), and superoxide dismutase (SOD). Fluorescence quantitative PCR was used to detect the mRNA expression of brain-derived neurotrophic factor (BDNF), tyrosine kinase receptor B (TrkB), and inducible nitric oxide synthase (iNOS) in the hippocampus, and western blot was performed to detect protein expression levels related to the NF-κB signaling pathway in the hippocampus. RESULTS: Compared with the normal control group, CUMS significantly induced abnormal behaviors in stressed rats. The concentrations of pro-inflammatory factors and oxidative stress injury factors in the hippocampus of the CUMS group increased significantly. The interventions of Flu, WIN, and PDTC significantly reduced neuroinflammation and oxidative stress injury. Compared with the WIN group, the WIN + PDTC intervention group had better results. In addition, WIN could significantly inhibit the activation of the NF-κB signaling pathway. CONCLUSIONS: This study showed that cannabinoid receptor agonists can reduce the CUMS-induced depressive behaviors of rats by blocking the NF-κB signaling pathway to alleviate neuroinflammation and oxidative stress injury.

Effects of nicorandil on p120 expression in the spinal cord and dorsal root ganglion of rats with chronic postsurgical pain.

Chronic postsurgical pain (CPSP) has a high incidence, but the underlying mechanism is not well understood. Accumulating evidence has suggested that central sensitization is the main mechanism of pain. To study the role of p120 in CPSP, a skin/muscle incision and retraction (SMIR) model was established, and immunofluorescence staining and western blotting were performed to analyze the expression of p120 in the spinal cord and dorsal root ganglion (DRG). The results demonstrated that SMIR increased the expression of p120 in the DRG and the spinal cord compared with the naive group. Furthermore, it was demonstrated that p120 was mainly distributed in the glial fibrillary acidic protein­positive astrocytes in the spinal cord, and in the neurofilament 200­positive medium and large neurons in the DRG. Our previous studies have shown that adenosine triphosphate­sensitive potassium channel (KATP) agonists can reduce postoperative pain in rats. Therefore, the changes in p120 were observed in the DRG and spinal cord of rats following the intraperitoneal injection of nicorandil, a KATP agonist. It was demonstrated that nicorandil administration could relieve mechanical pain experienced following SMIR in rats, and decrease the expression of p120 in the DRG and spinal cord. The results revealed that p120 may contribute to the prophylactic analgesic effect of nicorandil, thus providing a novel insight into the mechanism of CPSP prevention.

Role of p120 Catenin in Epac1-Induced Chronic Postsurgical Pain in Rats.

Chronic postsurgical pain (CPSP) is a chronic pain state that is difficult to be treated clinically. A series of complicated changes have been produced from nociceptive stimulation to the occurrence and development of postsurgical pain. Many mechanisms remain unclear. In order to study the role of intercellular gap junctions in inducing inflammatory microenvironment at the beginning of nociceptor after operation, the model of skin/muscle incision and retraction (SMIR) was established. We observed the changes of the expression of exchange proteins directly activated by cAMP-1 (Epac1) and p120 catenin (p120), the quantities of macrophages and endothelial cells, vascular endothelial permeability, and mechanical withdrawal threshold (MWT). It was found that macrophages and endothelial cells were functionally coupled through Epac1-p120. Adhesive linkage disorder remodeled the chronic, inflammatory, and eutrophic microenvironment at the beginning of nociceptor after operation through macrophages, endothelial cells, and endothelial paracellular pathways. It might be an early event and a key step in peripheral sensitization of CPSP. The expression of p120 in muscle tissue around the incision might become a prognostic marker for the conversion of acute postsurgical pain into CPSP. Targeted intervention of Epac1-p120 might be a clinical strategy for inhibiting the conversion of acute postsurgical pain into CPSP.

Complete genome sequence of porcine parvovirus N strain isolated from guangxi, china.

We report here the complete genomic sequence of the porcine parvovirus (PPV) N strain, isolated in 1989 from the viscera of a stillborn fetus farrowed by a gilt in Guangxi, southern China. Phylogenetic analyses suggest that the PPV-N strain is closely related to attenuated PPV NADL-2 strains. The PPV-N strain has good immunogenicity, genetic stability, and safety.