General anesthesia vs. conscious sedation and local anesthesia for endovascular treatment in patients with posterior circulation acute ischemic stroke: An updated systematic review and meta-analysis.

INTRODUCTION: The best anesthetic choice for patients with acute posterior circulation stroke during endovascular treatment (EVT) remains uncertain. METHOD: We searched five databases to identify studies that met the inclusion criteria. Our primary outcome measure was functional independence (FI). Secondary outcomes were 3-month mortality, any intracranial hemorrhage (ICH), symptomatic ICH (sICH), successful reperfusion, and procedure- and ventilator-associated complications. RESULTS: A total of 10 studies were included in our meta-analysis. No significant differences were detected between the general anesthesia (GA) and conscious sedation and local anesthesia (CS/LA) groups in 3-month FI (nine studies; OR=0.69; 95% CI 0.45-1.06; P=0.083; I2=66%;), 3-month mortality (nine studies; OR=1.41; 95% CI 0.94-2.11; P=0.096; I2=61.2%;), any ICH (three studies; OR=0.75; 95% CI 0.44-1.25; P=0.269; I2=0%;), or sICH (six studies; OR=0.64; 95% CI 0.40-1.04; P=0.073; I2=0%;). No significant differences were observed for successful reperfusion (10 studies; OR=1.17; 95% CI 0.91-1.49; P=0.219; I2=0%;), procedure-related complications (four studies; OR=1.14; 95% CI 0.70-1.87; P=0.603; I2=7.9%;), or respiratory complications (four studies; OR=1.19; 95% CI 0.61-2.32; P=0.616; I2=64.9%;) between the two groups. CONCLUSIONS: Our study showed no differences in 3-month FI, 3-month mortality, and successful reperfusion between patients treated with GA and those treated with CS/LA. Additionally, no increased risk of hemorrhagic transformation or pulmonary infection was observed in the CS/LA group. These results indicate that CS/LA may be an EVT option for acute posterior circulation stroke patients.

TRPV1 and GABAB1 in the Cerebrospinal Fluid-Contacting Nucleus are Jointly Involved in Chronic Inflammatory Pain in Rats.

Objective: To assess the receptors of TRPV1 and GABAB1 receptors that were colocalized in cerebrospinal fluid contacting nucleus (CSF-contact nucleus) of chronic inflammatory pain (CIP) rats bringing inspiration for reducing chronic pain. Methods: A rat model of CIP was constructed by plantar injection of complete Freund's adjuvant (CFA), and the paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) were measured 1, 3, 5, 7, 10, and 14 days after plantar injection. In the first part of the experiment, rats with CIP were divided into the immunofluorescence group and the coimmunoprecipitation (Co-IP) group (n = 6). Rats in the immunofluorescence group were injected with the retrograde tracer CB conjugated with Alexa Fluor 594 into the lateral ventricle two days before the injection of CFA into the plantar surface of the left paw. Three days later, rats that exhibited hyperalgesia were perfused, and their brains were extracted and used for double immunofluorescence staining of the CSF-contacting nucleus. Rats in the Co-IP group were anesthetized and dissected 3 days after CFA injection, and fresh brain segments containing the CSF-contacting nucleus were collected for Co-IP to assess the colocalization of TRPV1 and GABAB1 in the CSF-contacting nucleus (n = 6). In the second part of the experiment, SD rats were divided into the normal saline group (control group) and the CFA group. Fresh CSF-contacting nucleus-containing tissues were collected for Western blot analysis 3 days after plantar injection to observe the changes in TRPV1 and GABAB1 expression in the CSF-contacting nucleus. Results: TRPV1 and GABAB1 were co-expressed in the CSF-contacting nucleus in rats with CIP, and their expression was upregulated. Conclusion: TRPV1 and GABAB1 in the CSF-contacting nucleus are jointly involved in CIP in rats, and there is a direct or indirect link between TRPV1 and GABAB1.

[The distribution of Mas-related G protein-coupled receptor A in cerebrospinal fluid-contacting nucleus of normal rats and its up-regulation in neuropathic pain].

This study was aimed to observe the distribution of Mas-related G protein-coupled receptor A (MrgA) in cerebrospinal fluid (CSF)-contacting nucleus of normal rats and its expression in neuropathic pain, and to provide morphological evidence for CSF-contacting nucleus to participate in neuropathic pain. The model of neuropathic pain with chronic constriction injury (CCI) of the sciatic nerve was made in Sprague-Dawley rats. The thermal withdrawal latency (TWL) and mechanical withdrawal threshold (MWT) were measured. The expressions of MrgA in the CSF-contacting nucleus were examined by double labeling with immunofluorescent staining. The results showed that on the 5th, 7th, 10th and 14th days, the values of MWT and TWL in CCI group were all lower than those in sham group (P < 0.05). MrgA was found to be distributed in CSF-contacting nucleus of normal rats; and the expression was markedly up-regulated in rats at the peak of neuropathic pain. Our data suggest that CSF-contacting nucleus may participate in neuropathic pain through the MrgA-mediated signaling pathway.

GluN2B-BDNF pathway in the cerebrospinal fluid-contacting nucleus mediates nerve injury-induced neuropathic pain in rats.

The present study was aimed to investigate the role of GluN2B-BDNF pathway in the cerebrospinal fluid-contacting nucleus (CSF-CN) in neuropathic pain. Intra-lateral ventricle injection of cholera toxin subunit B conjugated with horseradish peroxidase (CBHRP) was used to label the CSF-CN. Double-labeled immunofluorescent staining and Western blot were used to observe the expression of GluN2B and BDNF in the CSF-CN. Chronic constriction injury of sciatic nerve (CCI) rat model was used to duplicate the neuropathic pain. Pain behavior was scored to determine the analgesic effects of GluN2B antagonist Ro 25-6981 and BDNF neutralizing antibody on CCI rats. GluN2B and BDNF were expressed in the CSF-CN and their expression was up-regulated in CCI rats. Intra-lateral ventricle injection of GluN2B antagonist Ro 25-6981 or BDNF neutralizing antibody notably alleviated thermal hyperalgesia and mechanical allodynia in CCI rats. Moreover, the increased expression of BDNF protein in CCI rats was reversed by intra-lateral ventricle injection of Ro 25-6981. These results suggest that GluN2B and BDNF are expressed in the CSF-CN and alteration of GluN2B-BDNF pathway in the CSF-CN is involved in the modulation of the peripheral neuropathic pain.

The CSF-Contacting Nucleus Receives Anatomical Inputs From the Cerebral Cortex: A Combination of Retrograde Tracing and 3D Reconstruction Study in Rat.

OBJECTIVE: This study aimed to investigate the direct monosynaptic projections from cortical functional regions to the cerebrospinal fluid (CSF)-contacting nucleus for understanding the functions of the CSF-contacting nucleus. METHODS: The Sprague-Dawley rats received cholera toxin B subunit (CB) injections into the CSF-contacting nucleus. After 7-10 days of survival time, the rats were perfused, and the whole brain and spinal cord were sliced under a freezing microtome at 40 µm. All sections were treated with the CB immunofluorescence reaction. The retrogradely labeled neurons in different cortical areas were revealed under a confocal microscope. The distribution features were further illustrated under 3D reconstruction. RESULTS: The retrogradely labeled neurons were identified in the olfactory, orbital, cingulate, insula, retrosplenial, somatosensory, motor, visual, auditory, association, rhinal, and parietal cortical areas. A total of 12 functional areas and 34 functional subregions showed projections to the CSF-contacting nucleus in different cell intensities. CONCLUSION: According to the connectivity patterns, we conclude that the CSF-contacting nucleus participates in cognition, emotion, pain, visceral activity, etc. The present study firstly reveals the cerebral cortex→CSF-contacting nucleus connections, which implies the multiple functions of this special nucleus in neural and body fluid regulations.

A Special Cranial Nucleus (CSF-Contacting Nucleus) in Primates.

BACKGROUND: There is a unique nucleus (CSF-contacting nucleus) in the brain of rat. It has been demonstrated in our previous research. The extraordinary feature of this nucleus is that it is not connected to any parenchymal organ but to the CSF. In primates, however, the presence or absence of this nucleus has not been proven. Confirmation of the presence of this nucleus in primates will provide the structural basis for brain-CSF communication and help to understand the neurohumoral regulatory mechanisms in humans. METHODS: The tracer cholera toxin B subunit conjugated to horseradish peroxidase (CB-HRP) was injected into the CSF in the lateral ventricle (LV) of primate rhesus monkeys. After 48 h, the monkeys were perfused and the brain was dissected out, and sectioned for CB-HRP staining. The CB-HRP positive structures were observed under confocal and electron microscopy. The three-dimensional (3D) structure of the CB-HRP positive neurons cluster was reconstructed by computer software. RESULTS: (1) CB-HRP labeling is confined within the ventricle, but not leakage into the brain parenchyma. (2) From the midbrain inferior colliculus superior border plane ventral to the aqueduct to the upper part of the fourth ventricle (4V) floor, a large number of CB-HRP positive neurons are consistently located, form a cluster, and are symmetrically located on both sides of the midline. (3) 3D reconstruction shows that the CB-HRP positive neurons cluster in the monkey brain occupies certain space. The rostral part is large and caudal part is thin appearing a "rivet"-like shape. (4) Under electron microscopy, the CB-HRP positive neurons show different types of synaptic connections with the non-CSF-contacting structures in the brain. Some of the processes stretch directly into the ventricle cavity. CONCLUSION: Same as we did in rats, the CSF-contacting nucleus is also existed in the primate brain parenchyma. We also recommend listing it as the XIII pair of cranial nucleus, which is specialized in the communications between the brain and the CSF. It is significant to the completing of innervation in the organism.

Novel Projections to the Cerebrospinal Fluid-Contacting Nucleus From the Subcortex and Limbic System in Rat.

Objective: To identify the novel projections received by the cerebrospinal fluid (CSF)-contacting nucleus from the subcortex and limbic system to understand the biological functions of the nucleus. Methods: The cholera toxin subunit B (CB), a retrograde tracer, was injected into the CSF-contacting nucleus in Sprague-Dawley rats. After 7-10 days, the surviving rats were perfused, and the whole brain and spinal cord were sliced for CB immunofluorescence detection. The CB-positive neurons in the subcortex and limbic system were observed under a fluorescence microscope, followed by 3D reconstructed with the imaris software. Results: CB-positive neurons were found in the basal forebrain, septum, periventricular organs, preoptic area, and amygdaloid structures. Five functional areas including 46 sub-regions sent projections to the CSF-contacting nucleus. However, the projections had different densities, ranging from sparse to moderate, to dense. Conclusions: According to the projections from the subcortex and limbic system, we hypothesize that the CSF-contacting nucleus participates in emotion, cognition, homeostasis regulation, visceral activity, pain, and addiction. In this study, we illustrate the novel projections from the subcortex and limbic system to the CSF-contacting nucleus, which underlies the diverse and complicated circuits of the nucleus in body regulations.

Connection Input Mapping and 3D Reconstruction of the Brainstem and Spinal Cord Projections to the CSF-Contacting Nucleus.

Objective: To investigate whether the CSF-contacting nucleus receives brainstem and spinal cord projections and to understand the functional significance of these connections. Methods: The retrograde tracer cholera toxin B subunit (CB) was injected into the CSF-contacting nucleus in Sprague-Dawley rats according the previously reported stereotaxic coordinates. After 7-10 days, these rats were perfused and their brainstem and spinal cord were sliced (thickness, 40 µm) using a freezing microtome. All the sections were subjected to CB immunofluorescence staining. The distribution of CB-positive neuron in different brainstem and spinal cord areas was observed under fluorescence microscope. Results: The retrograde labeled CB-positive neurons were found in the midbrain, pons, medulla oblongata, and spinal cord. Four functional areas including one hundred and twelve sub-regions have projections to the CSF-contacting nucleus. However, the density of CB-positive neuron distribution ranged from sparse to dense. Conclusion: Based on the connectivity patterns of the CSF-contacting nucleus receives anatomical inputs from the brainstem and spinal cord, we preliminarily conclude and summarize that the CSF-contacting nucleus participates in pain, visceral activity, sleep and arousal, emotion, and drug addiction. The present study firstly illustrates the broad projections of the CSF-contacting nucleus from the brainstem and spinal cord, which implies the complicated functions of the nucleus especially for the unique roles of coordination in neural and body fluids regulation.

Monosynaptic Input Mapping of Diencephalic Projections to the Cerebrospinal Fluid-Contacting Nucleus in the Rat.

Objective: To investigate the projections the cerebrospinal fluid-contacting (CSF-contacting) nucleus receives from the diencephalon and to speculate on the functional significance of these connections. Methods: The retrograde tracer cholera toxin B subunit (CB) was injected into the CSF-contacting nucleus in SD rats according to the experimental formula of the stereotaxic coordinates. Animals were perfused 7-10 days after the injection, and the diencephalon was sliced at 40 µm with a freezing microtome. CB-immunofluorescence was performed on all diencephalic sections. The features of CB-positive neuron distribution in the diencephalon were observed with a fluorescence microscope. Results: The retrograde labeled CB-positive neurons were found in the epithalamus, subthalamus, and hypothalamus. Three functional diencephalic areas including 43 sub-regions revealed projections to the CSF-contacting nucleus. The CB-positive neurons were distributed in different density ranges: sparse, moderate, and dense. Conclusion: Based on the connectivity patterns of the CSF-contacting nucleus that receives anatomical inputs from the diencephalon, we preliminarily assume that the CSF-contacting nucleus participates in homeostasis regulation, visceral activity, stress, emotion, pain and addiction, and sleeping and arousal. The present study firstly illustrates the broad projections of the CSF-contacting nucleus from the diencephalon, which implies the complicated functions of the nucleus especially for the unique roles of coordination in neural and body fluids regulations.

Knockdown of the Long Noncoding RNA LUCAT1 Inhibits High-Glucose-Induced Epithelial-Mesenchymal Transition through the miR-199a-5p-ZEB1 Axis in Human Renal Tubular Epithelial Cells.

Renal fibrosis, the leading cause of end-stage renal disease and in which epithelial-mesenchymal transition (EMT) plays a central role, has a complex pathogenesis that is not fully understood. Therefore, we investigated the role of the long noncoding RNA LUCAT1 in the EMT of renal tubular epithelial cells under high-glucose (HG) conditions and the underlying mechanism involved. In this study, we established HG and normal glucose groups of HK-2 cells by treating HK-2 cells 30.0 or 5.5 mmol/L glucose, respectively. To investigate the roles of LUCAT1 and miR-199a-5p in HG-induced EMT, we transfected the HG group with negative control small interfering RNA (siRNA), siRNA targeting LUCAT1, negative control microRNA, or an miR-199a-5p mimic. The results of the quantitative reverse transcription PCR indicated that the LUCAT1 level in the HG group was increased, whereas the miR-199a-5p level was decreased. The EMT in the cells was induced by treatment with HG but was weakened by LUCAT1 knockdown or miR-199a-5p overexpression, which both also inhibited the HG-induced phosphorylation of SMAD3. Moreover, LUCAT1 and ZEB1 mRNA comprised the same microRNA response elements of miR-199a-5p. LUCAT1 knockdown had no effect on the miR-199a-5p level but decreased the HG-induced upregulation of ZEB1. In conclusion, HG conditions induced the upregulation of LUCAT1, and LUCAT1 knockdown inhibited the EMT in HG-treated HK-2 cells. LUCAT1 likely promotes HG-induced EMT through ZEB1 by sponging miR-199a-5p.

Stereotaxic Coordinates and Morphological Characterization of a Unique Nucleus (CSF-Contacting Nucleus) in Rat.

A unique nucleus, the cerebrospinal fluid (CSF)-contacting nucleus, has recently been recognized in the brain parenchyma. The outstanding feature of this nucleus is that the neural somas are located in the parenchyma, but their processes stretch into the CSF, implying that it may be a key structure bridging the nervous and body fluids-regulating systems and may play a pivotal role in modulating physiological activities. However, the true biological significance of this nucleus needs to be uncovered. The morphology of a nucleus is one of the most important parameters for neuroscience studies. For this reason, a common experimental animal, Sprague-Dawley (SD) rats, was chosen. The position, adjacent structures, neuronal distribution, size, three-dimensional reconstruction, and core coordinates of the CSF-contacting nucleus in SD rats of different weights (90-400 g) were illustrated for the first time. Furthermore, the formulas for calculating the core coordinates of the CSF-contacting nucleus in rats of different weights were revealed. Finally, the possible biological functions uncovered by past research are reviewed in this paper. This study provides an indispensable methodology and a significant reference for researchers interested in this unique nucleus.

The Establishment of a CSF-Contacting Nucleus "Knockout" Model Animal.

To establish an entirely cerebrospinal fluid (CSF)-contacting nucleus-deficient model animal, we used cholera toxin B subunit (CB)- saporin (SAP), which is an analog of CB-HRP that specifically labels the CSF-contacting nucleus, to exclusively damage the nucleus. The effectiveness and specificity of the ablation were evaluated upon days 1-10 after CB-SAP microinjection into the brain ventricular system. The vital status, survival, and common physiological parameters of the model animals were also assessed during the experimental period. The results demonstrated that CB-SAP damaged only the CSF-contacting nucleus, but not other functional structures, in the brain. The complete ablation occurred by day 7 after CB-SAP microinjection. A model animal that had no CSF-contacting nucleus was established after survival beyond that time point. No obvious effects were observed in the vital status of the model animals, and their survival was ensured. The common physiological parameters of model animals were stable. The present study provides a method to establish a CSF-contacting nucleus "knockout" model animal, which is similar to a gene knockout model animal for studying this particular nucleus in vivo.

Activation of P2X3 receptors in the cerebrospinal fluid-contacting nucleus neurons reduces formalin-induced pain behavior via PAG in a rat model.

The cerebrospinal fluid (CSF)-contacting nucleus is implicated in the descending inhibitory pathway in pain processing, whereas the cellular and molecular mechanisms underpinning CSF-contacting nucleus regulating pain signals remains largely elusive. ATP is evidenced to inhibit pain transmission at supraspinal level by the mediation of the receptor P2X, wherein its subtype P2X3 is identified as the most potent. Our present experiment investigated the functionality of P2X3 receptors in CSF-contacting nucleus in the formalin-evoked inflammatory pain. Immunofluorescence and western blot revealed the expression of P2X3 receptors in the CSF-contacting nucleus and their upregulated expression subsequent to administration of formalin in rat model. ATP (a P2X3 receptor agonist, 100nmol/5µl) by intracerebroventricular (i.c.v.) administration ameliorated pain behaviors and enhanced c-Fos immunoreactivity in the neurons of the periaqueductal gray (PAG), both of which were discounted by pre-administration of A-317491 (a selective P2X3 receptor antagonist, 25nmol/5µl). After the CSF-contacting nucleus was ablated by cholera toxin subunit B-saporin, ATP failed to induce analgesia, with the c-Fos immunoreactivity in the PAG neurons remaining intact. Our results validated that P2X3 receptors in the CSF-contacting nucleus are pivotal in inflammatory pain processing via the activation of PAG neurons.

[Phosphorylation of protein kinase C in cerebrospinal fluid-contacting nucleus modulates the inflammatory pain in rats].

The present study was aimed to investigate the role of cerebrospinal fluid-contacting nucleus (CSF-CN) neurons in modulation of inflammatory pain and underlying mechanism. The inflammatory pain model was made by subcutaneous injection of the complete Freund's adjuvant (CFA) into the left hind paw of rats. The phosphorylation level of PKC (p-PKC) was examined by Western blot. Thermal withdrawal latency (TWL) of the rats was measured to assess inflammatory pain. The results showed that, compared with the sham controls, the inflammatory pain model rats showed shortened TWL on day 1, 3, and 7 after CFA injection, as well as increased level of p-PKC in CSF-CN neurons at 24 h after CFA injection. The administration of GF109203X, a PKC inhibitor, into lateral ventricle decreased the level of p-PKC protein expression and increased TWL in the model rats. These results suggest that blocking the PKC pathway in CSF-CN neurons may be an effective way to reduce or eliminate the inflammatory pain.

Extracellular Signal-Regulated Kinase 5 in the Cerebrospinal Fluid-Contacting Nucleus Contributes to Neuropathic Pain in Rats.

BACKGROUND: The activation of mitogen-activated protein kinases (MAPKs) have been observed in synaptic plasticity processes of learning and memory in neuropathic pain. Cerebrospinal fluid-contacting nucleus (CSF-CN) has been identified with the onset and persistence of neuropathic pain. However, whether extracellular signal-regulated protein kinase 5 (ERK5), a member of MAPKs, in CSF-CN participates in neuropathic pain has not been studied yet. OBJECTIVE: The aim of the present study was to identify the role of ERK5 in CSF-CN on the formation and development of neuropathic pain, and to investigate its possible mechanism. STUDY DESIGN: Controlled animal study. SETTING: University laboratory. METHODS: After a chronic constriction injury (CCI) model was produced, BIX02188 was dissolved in 1% DMSO and injected into the lateral ventricles LV in a volume of 3 µl with different doses (0.1 µg, 1 µg, 10 µg). Mechanical allodynia and thermal hypersensitivity behavioral test, immunofluorescence, and western blot technique were used in this research. RESULT: Following CCI, mechanical allodynia and thermal hypersensitivity were developed within a day, peaked at 14 days, and persisted for 21 days. ERK5 was remarkably activated by CCI in CSF-CN. Moreover, selective inhibiting of p-ERK5 expression in CSF-CN by BIX02188 could significantly relieve CCI-induced mechanical allodynia and thermal hypersensitivity, accompanying with the decreased phosphorylation of cAMP response-element binding protein (CREB) in CSF-CN. LIMITATIONS: More underlying mechanism(s) of the role of ERK5 in CSF-CN on the formation and development of neuropathic pain will be needed to explore in future research. CONCLUSION: These findings suggest activation of ERK5 in CSF-CN might contribute to the onset and development of neuropathic pain and its role might be partly accomplished by p-CREB.

Role of adrenomedullin in the cerebrospinal fluid-contacting nucleus in the modulation of immobilization stress.

The contribution of the cerebrospinal fluid-contacting nucleus (CSF-contacting nucleus) and adrenomedullin (ADM) to the developmental modulation of stressful events remains controversial. This study explored the effects of endogenous ADM in the CSF-contacting nucleus on immobilization of stress-induced physiological parameter disorders and glucocorticoid hormone releasing hormone (CRH), rat plasma corticosterone expression, and verification of such effects by artificially lowering ADM expression in the CSF-contacting nucleus by targeted ablation of the nucleus. Immunohistochemical experiments showed that ADM-like immunoreactivity and the calcitonin receptor-like receptor (CRLR) marker were localized in the CSF-contacting nucleus. After 7 continuous days of chronic immobilization stress (CIS), animals exhibited anxiety-like behavior. Also, an increase in serum corticosterone, and enhanced expression of ADM in the CSF-contacting nucleus were observed, following activation by CIS. The intracerebroventricular (i.c.v.) administration of the ADM receptor antagonist AM22-52 significantly reduced ADM in the CSF-contacting nucleus, additionally, blocked the effects of ADM, meaning the expression of CRH in the hypothalamic paraventricular nucleus (Pa) and serum corticosterone level were increased, and the physiological parameters of the rats became correspondingly deteriorated. Additionally, the i.c.v. administration of cholera toxin subunit B-saporin (CB-SAP), a cytotoxin coupled to a cholera toxin subunit, completely eliminated the CSF-contacting nucleus, worsening the reaction of the body to CIS. The collective results demonstrated that ADM acted as a stress-related peptide in the CSF-contacting nucleus, and its lower expression and blocked effects in the nucleus contributed to the deterioration of stress-induced physiologic parameter disorders as well as the excessive expressions of stress-related hormones which were part of the hypothalamic-pituitary-adrenal (HPA) axis.

[The distribution of MAP kinase phosphatase-1 in the cerebrospinal fluid-contacting nucleus and its functional contribution to depressive behaviors].

The purpose of this research is to explore the distribution and expression of MAP kinase phosphatase-1 (MKP-1) in cerebrospinal fluid (CSF)-contacting nucleus in depression, and provide experimental evidence to reveal the biological function and regulatory mechanisms of CSF-contacting nucleus in depression. Depression model was produced by chronic forced swimming stress (CFSS) in Sprague-Dawley (SD) rats. Intracerebroventricular injection of cholera toxin subunit B (CTb) labeled with horseradish peroxidase (CB-HRP) was used to specifically mark distal CSF-contacting nucleus. The rate of animal growth and behavioral tests including sucrose preference test (SPT) and open field test (OFT) were used to validate the model of depression. The expressions of MKP-1 and fos proteins in CSF-contacting nucleus were detected by immunofluorescence. Software Image-Pro Plus version 6.0 was used to count the positive neurons. The results showed that, the distributions of MKP-1 were found in the CSF-contacting nucleus. After 28 days of swimming, the rats in stress group had a lower growth rate, a less consumption of sucrose and lower scores of OFT compared to control group. The number of neurons double labeled with CB-HRP/fos or CB-HRP/MKP-1 in stress group was significantly higher than that in control group (P < 0.01). These results suggest that the CSF-contacting nucleus may be involved in the process of depression via the MKP-1.

BDNF/TRK/KCC2 pathway in nicotine withdrawal-induced hyperalgesia.

PURPOSE: To investigate the effect of brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase (Trk) on potassium chloride cotransporter 2 (KCC2) in rats following nicotine withdrawal and the roles played by BDNF/Trk/KCC2 pathway in nicotine withdrawal-induced hyperalgesia. METHODS: Seventy-eight rats were randomly assigned to five groups: control group (n = 12) without any treatment, normal saline group (NS group, n = 12) and nicotine withdrawal group (NW group, n = 30) receiving a subcutaneous injection of saline or nicotine for 7 days, respectively. The NW + dimethyl sulfoxide (DMSO) (n = 12) and NW+ Trk antagonist K252a groups (n = 12) received an intrathecal injection of DMSO (10 µl) and K252a (10 µg/10 µl) for 3 days after nicotine withdrawal, respectively. Nicotine withdrawal was precipitated by subcutaneous injection of nonselective and noncompetitive antagonist of nicotinic acetylcholine receptors mecamylamine. Pain was tested using thermal withdrawal latency (TWL). A Western blot was used to examine the expression of BDNF and KCC2. RESULTS: The TWL was significantly decreased in NW group relative to control and NS groups (P < 0.01). Compared with the NW group, the NW+K252a group manifested a significantly higher latency (P < 0.01). The BDNF expression was increased and KCC2 was decreased in NW group compared with the control group (P < 0.01). K252a reduced KCC2 downregulation. CONCLUSION: BDNF/Trk signaling may contribute to nicotine withdrawal-induced hyperalgesia via downregulation of KCC2.

[Targeted damage of the cerebrospinal fluid-contacting nucleus contributes to the pain behavior and the expression of 5-HT and c-Fos in spinal dorsal horn of rats].

OBJECTIVE: The changes of pain threshold and expression of 5-hydroxytryptamine(5-HT) and c-Fos in spinal dorsal horn of rats were observed after targetedly damaged the cerebraspinal fluid-contacting nucleus (CSF-contacting nucleus) to provide experimental evidence for the mechanism of regulating pain CSF-contacting nucleus involved in. METHODS: Male adult SD rats were divided into control, sham, choleratoxin subunit B conjugated with horse-radish peroxidase (CB-HRP)and damage groups randomly. The pain threshold using mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were recorded and analyzed. Immunofluorescence method was used to observe the expression of 5-HT and c-Fos in spinal dorsal horn. RESULTS: Compared with the control, sham and CB-HRP groups, the MWT and TWL of the damage group were significantly increased (P < 0.05). The results of immunofluorescence showed that 5-HT was detected in neurons of CSF-contacting nucleus. In the damage group, the number of neurons of CSF-contacting nucleus reduced gradually, and no survived neurons were observed at the 10th day. Meanwhile, both the expression of 5-HT and c-Fos in spinal dorsal horn increased gradually, and negatively correlated with the change of pain threshold. CONCLUSION: The method of targeted damaging CSF-contacting nucleus by cholera toxin subnit B conjugated with saporin(CB-SAP) is scientific and reliable, and it results in the changes of pain threshold and expression of 5-HT and c-Fos in spinal dorsal horn of rats. This study suggests that CSF-contacting nucleus participate in the regulation of pain, moreover, 5-HT and c-Fos play important roles in this regulation.

[HCN ion channel: biological characteristics and functions in pain].

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in vertebrate are reverse voltage-dependent, and its activation depends on the hyperpolarization of cell and may be directly or indirectly regulated by the cyclic adenosine monophosphate (cAMP) or other signal transduction cascades. The distribution, quantity, and activation states of HCN channels differ in tissues throughout the body. By modulating If/If current, HCN channels may influence the resting membrane potential, and thus importantly regulate neuronal excitability, dendritic integration of synaptic potentials, and synaptic transmission. Evidence exhibits that HCN channels participate in pain and other physiological and pathological process. Pharmacological treatment targeting HCN channels is of benefit to relieve pain and other related diseases.