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ABSTRACT: The cerebrospinal fluid-contacting nucleus (CSF-CN) may influence actual composition of the CSF for non-synaptic signal transmission via releasing or absorbing bioactive substances, which distributes and localizes in the ventral periaqueductal central gray of the brainstem. Previous studies demonstrated that CSF-CN was involved in neuropathic pain and morphine dependence. Thus, to identify whether extracellular signal-regulated kinase 5 (ERK5) distributed in the CSF-CN and its function on the formation and development of morphine physical dependence, morphine withdrawal-like behavioral test and immunofluorescent technique were used in this research. Morphine was subcutaneously injected by an intermittent and escalating procedure to induce physical dependence, which was measured by withdrawal symptoms. In this study, we found that horseradish peroxidase-conjugated toxin subunit B/p-ERK5 double-labeled neurons expressed in the CSF-CN of normal rats. ERK5 signaling pathway was remarkably activated by naloxone-precipitated withdrawal in the CSF-CN. Moreover, selective attenuation of p-ERK5 expression in the CSF-CN by lateral ventricle injection of BIX02188 could significantly relieve morphine withdrawal symptom. These findings confirmed that the activation of p-ERK5 in the CSF-CN might contribute to morphine physical dependence.
Journal of Molecular Neuroscience 11/2012; · 2.50 Impact Factor
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ABSTRACT: To investigate the role of cerebrospinal fluid contacting nucleus (CSF-CN) and the changes of TRPC6 expression in morphine dependence and withdrawal. Male Sprague-Dawley rats (250 ± 50 g) were randomly divided into four groups: the normal group (N); the saline group (S); the morphine dependence group (D); the morphine withdrawal group (W). All animals in each group were tested the morphine withdrawal-like behavioral signs by total withdrawal scores. Double-labeled immunofluorescent technique and laser scanning confocal microscopy were used to identify the expression of TRPC6 in CSF-CN. TRPC6 labeled neurons were found in CSF-CN and the number of CB-HRP/TRPC6 double labeled neurons in CSF-CN significantly increased. TRPC6 existed in CSF-CN of the normal rats and its expression in morphine dependence and withdrawal increased. CSF-CN might participate in the development of morphine dependence and withdrawal by the up-regulated expression of TRPC6.
Neurochemical Research 08/2011; 36(12):2316-21. · 2.24 Impact Factor
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ABSTRACT: The activation of mitogen-activated protein kinases (MAPKs) has been observed in synaptic plasticity processes of learning and memory in morphine dependence. However, the role of extracellular signal-regulated protein kinase 5 (ERK5), a member of MAPKs, has not been studied yet in morphine dependence. To identify the function of ERK5 in the formation and development of morphine physical dependence, morphine withdrawal-like behavioral test and western blot technique were used in this research. Morphine was subcutaneously injected by an intermittent and escalating procedure to induce physical dependence, which was measured by withdrawal symptoms. In this study, spinal ERK5 signaling pathway was remarkably activated by chronic morphine injection and naloxone-precipitated withdrawal. Intrathecal injection of BIX02188, a novel specific inhibitor of mitogen-activated protein kinases kinase 5 (MEK5), produced a dose- and time-dependent inhibition of the activation of spinal ERK5, without affecting activation of other MAPKs. Moreover, selective attenuation of spinal p-ERK5 expression by BIX02188 could significantly relieve morphine withdrawal symptom, accompanying with the decreased phosphorylation of cAMP response-element binding protein (CREB) in the spinal cord. These findings suggested that activation of the ERK5 signaling pathway might contribute to morphine physical dependence and its specific pharmacological inhibitor BIX02188 could be a potential therapeutic choice for alleviation of morphine withdrawal symptoms in the future.
Neuroscience Letters 02/2011; 494(1):38-43. · 2.11 Impact Factor
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ABSTRACT: The cerebrospinal fluid-contacting nucleus (CSF-CN), distributes and localizes in the ventral periaqueductal central gray (PAG) of the brainstem, which may influence actual composition of the cerebrospinal fluid (CSF) for non-synaptic signal transmission via releasing or absorbing bioactive substances. Many experiments have demonstrated that substance P (SP), a substance that is shown to be up-regulated in CSF-CN, plays an important role in the development of inflammatory pain and neuropathic pain. Thus in the present study, we hypothesize that SP in CSF-CN might contribute to morphine dependence in rats, inhibiting SP with (D-Pro2, D-Phe7, D-Trp9)-SP intracerebroventricular (i.c.v.) injection reduce chronic morphine dependence and withdrawal. Rats were repeatedly injected with morphine in five escalating doses for morphine physical dependence. Morphine withdrawal-like behavioral signs and morphine analgesia behaviors were monitored after naloxone administration following i.c.v. injection of (D-Pro2, D-Phe7, D-Trp9)-SP. And SP-expression of CSF-CN was evaluated with dual-label immunofluorescent technique on morphine withdrawal in rats. After i.c.v. treatment with (D-Pro2, D-Phe7, D-Trp9)-SP, the naloxone-precipitated withdrawal symptoms were significantly attenuated, paw withdrawal threshold/thermal withdrawal latency (PWT/TWL) were increased, and SP-expression in CSF-CN was significantly reduced than control group. SP, known a neurotransmitter/neuromodulator of nociception, has also been implicated in the signs of opioid withdrawal. This study provides the first evidence that SP in CSF-CN contributes to morphine physical dependence and withdrawal, which may provide an important and specific role in mediating the motivational aspects of opiates withdrawal via CSF - the parenchyma of the brain, and may represent a novel pharmacological route such as SP inhibitor i.c.v. injection for the control of drug abuse.
Neuroscience Letters 01/2011; 488(2):188-92. · 2.11 Impact Factor
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ABSTRACT: Recent studies have shown that general anesthesia induces memory impairment. Sevoflurane, an inhalation anesthetic, is widely used in clinical practice, increasing pieces of evidence suggest that sevoflurane impairs memory processes due to changing gene expression in hippocampus. However, little is known about genome-widely analyzing the expression change induced by sevoflurane in hippocampus. In this study, we profiled the changes of hippocampal gene expression by microarray analysis. Six-week-old male Sprague-Dawley rats were anesthetized for 4h with 2.5% sevoflurane (n = 6) and were sacrificed 48 h later. RNA was extracted from the hippocampus for gene expression profile. Compared to control group, 417 genes, including up-regulated 67 and down-regulated 350, were significantly changed (> 2.0 or < -2.0 fold) (P < 0.05). Of these, there are 45 named genes, which are most involved in metabolism, development, biosynthesis, life material binding, location, signal transduction and communication, structural and vesicular processes. We randomly chose 6 differential genes to verify the microarray result. We also selected seven most differential genes, including 3 up-regulated genes (RMCP-1, Slc6a3, and Pitx2) and 4 down-regulated genes (VN7, AVP, IP10, and OT), to investigate whether there is a dose- or time-dependent effect of sevoflurane on gene expression. The result indicated that the microarray profile is reliable; there is no obvious dose-dependent effect of sevoflurane on gene expression. These results suggested that sevoflurane induced long-term (at least 2 days) expression change of the numerous genes in hippocampus, which may be related to the memory impairment or the other neural disorders.
Brain research 01/2011; 1381:124-33. · 2.46 Impact Factor
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ABSTRACT: Previous studies have demonstrated that QX-314, an intracellular sodium channel blocker, can enter into nociceptors through capsaicin-activated TRPV1 or permeation of the membrane by chemical enhancers to produce a sensory-selective blockade. However, the obvious side effects of these combinations limit the application of QX-314. A new strategy for targeting delivery of QX-314 into nociceptors needs further investigation. The aim of this study is to test whether acidic QX-314, when dissolves in acidic solution directly, can enter into nociceptors through acid-activated TRPV1 and block sodium channels from the intracellular side to produce a sensory-specific analgesic effect.
Acidic solution or noradrenaline was injected intraplantarly to induce acute pain behavior in mice. A chronic constrictive injury model was performed to induce chronic neuropathic pain. A sciatic nerve blockade model was used to evaluate the sensory-specific analgesic effects of acidic QX-314. Thermal and mechanical hyperalgesia were measured by using radiant heat and electronic von Frey filaments test. Spinal Fos protein expression was determined by immunohistochemistry. The expression of p-ERK was detected by western blot assay. Whole cell clamp recording was performed to measure action potentials and total sodium current in rats DRG neurons. We found that pH 5.0 PBS solution induced behavioral hyperalgesia accompanied with the increased expression of spinal Fos protein and p-ERK. Pretreatment with pH 5.0 QX-314, and not pH 7.4 QX-314, alleviated pain behavior, inhibited the increased spinal Fos protein and p-ERK expression induced by pH 5.0 PBS or norepinephrine, blocked sodium currents and abolished the production of action potentials evoked by current injection. The above effects were prevented by TRPV1 channel inhibitor SB366791, but not by ASIC channel inhibitor amiloride. Furthermore, acidic QX-314 employed adjacent to the sciatic nerve selectively blocked the sensory but not the motor functions in naïve and CCI mice.
Acid solution is a suitable medium for introducing QX-314 into nociceptors through TRPV1 channels to produce a sensory-specific analgesic effect.
PLoS ONE 01/2011; 6(12):e29395. · 4.09 Impact Factor
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Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology 02/2010; 26(1):36-8.
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ABSTRACT: To investigate whether the kainate (KA) receptor subunit GluR6 is involved in the acute inflammatory pain.
Formalin was injected into the mucosa of rectum in Sprague-Dawley rats to induce visceral pain. The antisense oligodeoxynucleotides (ODNs) of GluR6 were injected once per day for 3 d before formalin injection, after which GluR6 protein level was examined by immunoblotting method. The change of visceral pain was also investigated.
The expression of GluR6 in the spinal cord of rats increased after the formalin injection. Moreover, pre-treatment of GluR6 antisense ODNs could suppress GluR6 expression in the spinal cord of rats and decrease the scores of visceral pain at 45 min following formalin injection.
Kainate receptor subunit GluR6 plays an important role in the visceral pain induced by injection of formalin into the wall of rectum. GluR6 may serve as a potential target for the treatment of acute inflammatory visceral pain.
Neuroscience Bulletin 10/2009; 25(5):319-23. · 1.31 Impact Factor
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ABSTRACT: To investigate whether activation and translocation of extracellular signal-regulated kinase 5 (ERK5) is involved in the induction and maintenance of neuropathic pain and observe the effects of activation and translocation of ERK5 on the expression of phosphorylated cAMP response element binding (pCREB) in the chronic neuropathic pain.
Lumbar intrathecal catheters were chronically implanted in male Sprague-Dawley rats. The left sciatic nerve was loosely ligated proximal to the sciatica's trifurcation at approximately 1.0 mm intervals with 4-0 silk sutures. The phosphorothioate-modified antisense oligonucleotides (AS-ODNs) were intrathecally administered every 12 hours, 1 day pre-chronic constriction injury (CCI) and 3 day post-CCI. Thermal and mechanical nociceptive thresholds were assessed with the paw withdrawal latency to a radiant heat and von Frey filaments. Expressions of phosphorylated ERK5 (pERK5), pCREB, were assessed by both Western blotting and immunohistochemical analysis.
Intrathecal injection of ERK5 AS-ODN significantly attenuated CCI-induced mechanical allodynia and thermal hyperalgesia. CCI significantly increased the expression of pERK5 neurons in the ipsilateral spinal dorsal horn to injury, not in the contralateral spinal dorsal horn. The time courses of pERK5 expression showed that the levels of both cytosol and nuclear pERK5 were increased at all points after CCI and reached a peak level on post-operative day 5. CCI significantly increased the expression of pERK5 neurons in the laminae I and II of ipsilateral spinal dorsal horn to injury, not in the contralateral spinal dorsal horn. Phospho-CREB-positive neurons were distributed in all laminae of the bilateral spinal cord. Intrathecal injection AS-ODN markedly suppressed the increase of CCI-induced pERK5, pCREB expression in the spinal cord.
The activation of ERK5 pathways contributes to neuropathic pain in CCI rats, and the function of pERK5 may partly be accomplished via the CREB protein-dependent gene expression.
Neurological Research 06/2009; 31(10):1037-43. · 1.52 Impact Factor
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ABSTRACT: To investigate the changes of pCREB protein expression in the distal cerebrospinal fluid contacting neurons induced by chronic morphine dependence and withdrawal.
Twenty-four Sprague-Dawley rats of both genders were randomly divided into three groups (n=8 each): control (Group I); chronic morphine dependence (Group II); chronic morphine abstinence (Group III). Chronic morphine dependence was induced by increasing doses of morphine, starting from 5 to 260 mg/kg/day in 12 days. The animals were killed 24 hours later. We evaluated morphine dependence by measuring the behavioral expression of morphine withdrawal and pCREB double labeled neuron recordings of dorsal raphe nucleus. The CB-HRP/pCREB double labeling method was used to observe the expression of pCREB in the distal cerebrospinal fluid contacting neurons.
The results showed the number of double labeled neuron of distal cerebrospinal fluid contacting neuron in dorsal raphe nucleus with up-regulated expression.
Morphine-dependent and withdrawal can activate the distal cerebrospinal fluid contacting neurons phosphorylation CREB in rat brain. The cerebrospinal fluid contacting neuron is related to morphine withdrawal and dependence rats.
Neurological Research 01/2009; 31(7):738-42. · 1.52 Impact Factor
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ABSTRACT: To observe the expression of drebrin in the distal cerebrospinal fluid contacting neurons (dCSF-CNs) of rats with chronic constriction injury (CCI) of sciatic nerve by immunofluorescence technique, male Sprague-Dawley rats were randomly divided into three groups: control group, sham surgery group and CCI group. The behavior of rats was scored. After choleratoxin subunit B-conjugated horseradish peroxidase (CB-HRP, 3 muL) was injected into the lateral cerebroventricle to trace dCSF-CNs, the expression of drebrin was observed in the dCSF-CNs through immunofluorescence double staining and laser scanning confocal microscopy technique. The results showed that only the pain threshold of CCI group was decreased. The dCSF-CNs were clearly displayed in three groups. No drebrin expression was observed in the control and sham groups. In CCI group, drebrin was markedly expressed in intracytoplasm. It is suggested that the technique displaying dCSF-CNs with immunofluorescence is successful and the dCSF-CNs are possibly involved in the transmission of nociceptive information under the neuropathic pain state.
Sheng li xue bao: [Acta physiologica Sinica] 09/2008; 60(4):469-74.
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ABSTRACT: EphBs receptors and ephrinBs ligands are present in the adult brain and peripheral tissue and play a critical role in modulating multiple aspects of physiology and pathophysiology. Ours and other studies have demonstrated that spinal ephrinBs/EphBs signaling was involved in the modulation of nociceptive information and central sensitization. However, the role of ephrinBs/EphBs signaling in peripheral sensitization is poorly understood. This study shows that intraplantar (i.pl.) injection of ephrinB1-Fc produces a dose- and time-dependent thermal and mechanical hyperalgesia and the increase of spinal Fos protein expression in mice, which can be partially prevented by pre-treatment with EphB1-Fc. EphrinB1-Fc-induced hyperalgesia is accompanied with the NMDA receptor-mediated increase of expression in peripheral and spinal phosphorylated mitogen-activated protein kinases (phospho-MAPKs) including p-p38, pERK and pJNK, and also is prevented or reversed by the inhibition of peripheral and spinal MAPKs. Furthermore, in formalin inflammation pain model, pre-inhibition of EphBs receptors by the injection of EphB1-Fc reduces pain behavior, which is accompanied by the decreased expression of peripheral p-p38, pERK and pJNK. These data provide evidence that ephrinBs may act as a prominent contributor to peripheral sensitization, and demonstrate that activation of peripheral ephrinBs/EphBs system induces hyperalgesia through a MAPKs-mediated mechanism.
Pain 09/2008; 139(3):617-31. · 5.78 Impact Factor
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ABSTRACT: Calbindin-D28K is a calcium-binding protein in neuronal cytoplasm, which has the capability to protect neurons from degeneration. It was reported that glial cell line-derived neurotrophic factor (GDNF) increased calbindin-D28K expression in dopaminergic neurons in vitro. It was observed in our research that GDNF also enhanced the expression of calbindin-D28K in adult rat substantia nigra neurons in vivo. To investigate the intracellular signaling pathways underlying the calbindin-D28K expression induced by GDNF, immunoblot and immunoprecipitation analyses were performed in our present study. Our results showed that injection of GDNF alone into substantia nigra of an adult rat brain increased the calbindin-D28K expression; meanwhile, the phosphorylation level of protein kinase B (Akt) and extracellular signal-regulated kinase 1/2 (ERK1/2) increased. However, the calbindin-D28K expression induced by GDNF was specifically blocked by the inhibitor of phosphatidylinositol 3-kinase (PI3K), but the inhibitor of ERK1/2 did not block the calbindin-D28K expression. Furthermore, GDNF administration also caused the nuclear factor kappaB (NF-kappaB/p65), to translocate from cytoplasm into the nucleus, and the inhibitor of PI3K effectively blocked the translocation. Immunoprecipitation assay results further demonstrated that it was the p65/p52 complex of NF-kappaB, rather than the p65/p50 complex that translocated into the neuronal nucleus. The calbindin-D28K expression induced by GDNF was also inhibited when the NF-kappaB signaling pathway was blocked by Helenalin. These results described a novel mechanism by which the activation of PI3K/Akt-->NF-kappaB (p65/p52) signaling pathway could play a role in the calbindin-D28K expression induced by GDNF.
European Journal of Pharmacology 08/2008; 595(1-3):7-12. · 2.52 Impact Factor
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ABSTRACT: Activation of mitogen-activated protein kinases (MAPKs) in dorsal root ganglia (DRG) and the spinal dorsal horn contributes to inflammatory pain by transcription-dependent and -independent means. In this study, we investigated extracellular signal-regulated protein kinase 5 (ERK5) activation by peripheral inflammation in the spinal cord and DRG of rats and whether this activation contributes to a heat and mechanical hyperalgesia response. Injection of complete Freund's adjuvant (CFA) into a hindpaw produced persistent inflammation and sustained ERK5 activation in DRG and the spinal dorsal horn. Knockdown of the ERK5 by antisense oligonucleotides suppressed the heat and mechanical hyperalgesia. In addition, the antisense knockdown of ERK5 reduced CFA-induced phosphorylation of cAMP response-element binding protein (CREB), a downstream substrate of the ERK5 pathway, and expression of Fos, a marker for neuronal activation in the central nervous system. Our study suggests that activation of the ERK5 signaling pathway contributes to persistent hyperalgesia induced by peripheral inflammation.
Brain Research 07/2008; 1215:76-86. · 2.73 Impact Factor
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ABSTRACT: The possible involvement of the nitric oxide (NO)-cyclic GMP (cGMP)-protein kinase G (PKG) pathway on bovine lactoferrin (BLF)-induced spinal antihyperalgesic activity was elucidated in sciatic nerve injured rats. Intrathecal BLF reduced thermal hyperalgesia in a dose-dependent manner. Pretreatment with NG-L-nitro-arginine methyl ester (L-NAME, non-specific inhibitor of NO synthase), 7-nitroindazole (7-NI, neuronal NO synthase inhibitor), 1H-[1,2,4]-oxadiazolo [4,3-a] quinoxalin-1-one (ODQ, guanylyl-cyclase inhibitor), (9S, 10R, 12R)-2,3,9,10,11,12-hexahydro-10-methoxy-2, 9-dimethyl-1-oxo-9, 12-epoxy-1H-diindolo-[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid methyl ester (KT-5823, specific PKG inhibitor) or glybenclamide (ATP-sensitive K+ channel blocker), but not NG-D-nitro-arginine methyl ester (D-NAME, an inactive enantiomer of l-NAME), d-Phe-Cys-Tyr-d-Trp-Orn-Thr-NH2 (CTOP, selective mu-opioid receptor antagonist) or naloxone (nonselective opioid receptor antagonist) prevented BLF-induced antihyperalgesia. Data suggest that BLF-induced spinal antihyperalgesia could be due to activation of the NO-cGMP-PKG-K+ channel pathway and it is not mediated by mu-opioid receptor in a model of neuropathic pain.
Brain Research 06/2008; 1209:1-7. · 2.73 Impact Factor
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ABSTRACT: The present study aimed to explore the effects of 5-HT(1A) receptors in the distal cerebral spinal fluid-contacting neurons (CSF-CNs) in rat brain parenchyma in neuropathic pain. The model of neuropathic pain with chronic constriction injury (CCI) of the sciatic nerve was made in Sprague-Dawley rats. The behavioral studies of animal were scored and the paw withdrawal latency (PWL) and paw withdrawal threshold (PWT) were measured. The distribution and expression of 5-HT(1A) receptors were observed in the distal CSF-CNs in brain parenchyma with double labeling of cholera toxin subunit B with horseradish peroxidase (CB-HRP) and 5-HT(1A) receptors with immunhistochemistry. The relationship between 5-HT(1A) receptors in distal CSF-CNs and neuropathic pain was analyzed. The results were as follows. On days 1, 3, 7, 14 of neuropathic pain, the PWL was 19.37±2.74, 12.04±1.77, 8.74±1.15 and 12.31±1.94, respectively; the PWT was 18.58±3.62, 13.05±1.81, 6.66±1.43 and 11.55±2.01, respectively. CB-HRP-labeled neurons of two clusters were always found in definite region but not in other area in brain parenchyma. The number of neurons double-labeled with CB-HRP/5-HT(1A) receptors in each group was 276.14±36.00, 161.72±28.41, 108.64±6.81, and 139.76±44.64, which was about 95%, 60%, 40% and 55% of all CB-HRP-labeled neurons in the four courses of neuropathic pain, respectively. It is suggested that the distal CSF-CNs are always located in a special region in rat brain parenchyma and most of them have 5-HT(1A) receptors. A negative correlation is found between the expression of 5-HT(1A) receptors and neuropathic pain.
Sheng li xue bao: [Acta physiologica Sinica] 05/2008; 60(2):243-8.
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ABSTRACT: To observe the distribution and expression of p-p38MAPK in the distal cerebrospinal fluid contacting neurons in brain of rat by noise stress.
By a double-labelled method combing the tracing of CB-HRP and the immunohistochemical technique p-p38MAPK, the distribution and expression of p-p38MAPK in the distal cerebrospinal fluid contacting neurons(csf cn) were observed following noise stress. Expression of p-p38MAPK and double-labelled of CB-HRP/p-p38MAPK were also observed in rat brain after noise stress.
Two groups of CB-HRP labeled neuron clusters consistently appeared in certain regions of the brainstem but none in other regions of the brain. Without noise stress exposure, only a few neurons were found double-labeled by CB-HRP/p-p38MAPK. After 1 day noise stress exposure, only few neurons double-labeled by CB-HRP/p-p38MAPK were observed in the above-mentioned regions. After 5 days, the number of neurons double-labeled by CB-HRP/p-p38MAPK increased significantly compared with the control group (P < 0.05). After 10 days, the number of neurons double-labeled by CB-HRP/p-p38MAPK increased significantly compared with the control group (P < 0.05). After 20 days, both of the numbers of neurons double-labeled by CB-HRP/p-p38MAPK increased significantly compared with that of the control group (P < 0.01).
Two groups of distal cerebrospinal fluid contacting neuron clusters consistently existed in certain regions of the brain parenchyma, and in these clusters only a few neurons con rained p-p38MAPK. After noise stress exposure of different durations (days 1, 5, 10, 20), the number of distal cerebrospinal fluid contacting neurons with p-p38MAPK increased significantly with increasing days. The results indicate that distal cerebrospinal fluid contacting neurons are special neurons existing consistently in brain, including distal cerebrospinal fluid contacting neurons with p-p38MAPK which may participate in the whole procedure of signal transduction or central modulation in noise stress response and play greater roles with increasing days.
Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology 11/2007; 23(4):419-23.
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ABSTRACT: To investigate the effect of CSF contacting neurons (CSF-CNs) lesion in rat dorsal raphe nucleus (DRN) on the scores of morphine withdrawal symptoms precipitated by naloxone and the nNOS expression in dorsal horn of spinal cord, and study the relationship between the distal CSF-CNs in rat brain parenchyma and the development of morphine dependence and withdrawal.
Chemical lesion of neurons the injection of cholera toxin subunit B with horseradish peroxidase (CB-HRP) into one of the rats lateral ventricles, TMBST reaction, nNOS immunohistochemistry and Western blot were used in this study.
The withdrawal symptoms by the naloxone precipitated attenuated obviously after the lesion of CSF-CNs in rat DRN, scores of all signs were significantly decreased about 38% compared to that of withdrawal group without lesion (P < 0.05). The withdrawal symptoms scores of vehicle withdrawal group and side lesion withdrawal group were not changed significantly (P > 0.05). Neurons in the location of CSF-CNs concentrated in the rat brain slices of lesion group were damaged obviously, there were only few CB-HRP positive neurons around the lesion location. But the location and the quantity of the CB-HRP positive neurons in the brain slices of the group without lesion was stable relatively, and their appearance was very clear. After the lesion, the nNOS expression and the quantity of the nNOS positive neurons in dorsal horn of spinal cord decreased significantly compared to that of withdrawal group without lesion (P < 0.05), but it also increased significantly compared to that of normal group and dependence group (P < 0.01).
The lesion of distal CSF contacting neurons attenuated the scores of morphine withdrawal symptoms precipitated by naloxone and the nNOS expression in dorsal horn of spinal cord. The distal CSF contacting neurons in rat brain parenchyma partly participated in the development of morphine dependence and naloxone precipitated withdrawal possibly by the modulation of NO (nitric oxide).
Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology 08/2007; 23(3):286-91.
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Zhi-Jun Ge,
Chang Li, Li-Cai Zhang,
Yin-Ming Zeng,
Jun-Li Cao,
Ti-Jun Dai,
Jun-Ke Wang,
Guo-Xin Cui,
Yong-Fei Tan,
Yan-Ping Zhao,
Guo-Jun Liu
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ABSTRACT: It is well known that dorsal raphe nucleus (DRN) is one of the key structures for the development of opioid analgesia and tolerance. An increased activity of 'antiopioids' like orphanin-FQ (OFQ) has been proposed as a possible mechanism for opioid tolerance. The present study evaluates the role of DRN-located OFQ in the opioid analgesic tolerance induced by repeated microinjections of morphine (MOR) into DRN. Male rats were implanted with chronic guide cannulae aimed at the DRN. Microinjection of MOR (0.5 microg in 0.5 microl) into DRN caused antinociception as quantified with the tail flick and the hot plate tests. When MOR microinjection was repeated twice daily, the antinociceptive effect disappeared within 2 days (tolerance). However, if each MOR microinjection was preceded (within 15 min) by a microinjection of the OFQ receptor antagonist nocistatin (NST) (1 ng in 0.5 microl) into the same DRN site, the microinjections of MOR always produced antinociception and did not induce tolerance. If NST microinjections were suspended, subsequent MOR microinjections induced tolerance. In MOR-tolerant rats, a single NST microinjection into the same DRN site was enough to restore the antinociceptive effect of MOR. On the other hand, if OFQ (1 ng in 0.5 microl) was microinjected into DRN, then MOR microinjection administered 15 min later into the same DRN site did not elicit antinociception. Finally, opioid tolerance induced by repeated systemic MOR injections (5 mg/kg, i.p.) was reversed by a single microinjection of NST into DRN. This emphasizes the central importance of DRN-located OFQ in the MOR analgesic tolerance.
Neuroscience Letters 03/2007; 413(3):233-7. · 2.11 Impact Factor
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ABSTRACT: The present study evaluated the role of ventrolateral periaqueductal gray (vlPAG)-located orphanin-FQ (OFQ) in the opioid tolerance induced by repeated microinjections of morphine (MOR) into vlPAG. Microinjection of MOR (5 microg/0.5 microl) into vlPAG caused antinociception as quantified with the tail flick and the hot plate tests. When MOR microinjection was repeated twice daily, the antinociceptive effect disappeared within 2 days (tolerance). However, if MOR microinjection was preceded by the OFQ receptor antagonist nocistatin (NST; 1 ng/0.5 microl), the microinjections of MOR did not induce tolerance. If NST microinjections were suspended, subsequent MOR microinjections induced tolerance. In MOR-tolerant rats, a single NST microinjection into vlPAG was enough to restore the antinociceptive effect of MOR. Furthermore, if OFQ (1 ng/0.5 microl) was microinjected into vlPAG, then a MOR microinjection administered 15 min later into vlPAG did not elicit antinociception. Finally, opioid tolerance induced by repeated systemic MOR injections (5 mg/kg, i.p.) was reversed by a single microinjection of NST into vlPAG. This emphasizes the central importance of vlPAG-located OFQ in the MOR tolerance.
Pharmacology 02/2007; 80(4):261-8. · 1.79 Impact Factor
