Regulatory Effects of Ionotropic and GroupⅠ Metabotropic Glutamate Receptors on Temperature Hypersensitivity in Rats / 中国医科大学学报

Objective To study the effects of ionic and group Ⅰ metabotropic glutamate receptors on rats' thermal hypersensitivity by intraplantar administration of drugs. Methods After intraplantar administration of glutamate receptor agonists,L-glutamic acid (Glu), N-methyl-D-aspartic-acid (NMDA),and (RS)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid hydrobromide (AMPA);a Group Ⅰ mGluR agonist, (S) 3,5-dihydroxyphenylglycine [(S)-DHPG];a noncompetitive NMDA receptor antagonist, (+)-MK801 maleate (MK-801);a competitive AMPA/kainate receptor antagonist,6-cyano-7-nitroquinoxaline-2,3-dione (CNQX);and a selective GroupⅠ mGluR antagonist,7-hydroxyiminocyclo propan[b]chromen-1a- carboxylic acid ethyl ester (cpccoEt) into the left hind paws of rats whose L5-6 nerves were sham-operated or ligated,we examined the response of the rats to thermal stimuli provided by radiant heat. Results In sham-operated rats,glutamate,NMDA,AMPA,and (S)-DHPG reduced paw withdrawal latency (PWL) but did not have any effect on SNL rats. However,in SNL rats,MK-801,CNQX,and cpccoEt increased PWL but exerted no effect on sham-operated rats. Conclusion These results suggest that changes in sensitivity of peripheral ionic and group Ⅰ metabotropic glutamate receptors can lead to changes in peripheral nerve plasticity;the generation and maintenance of neuropathic pain caused by nerve injury is based on this plasticity.

Metabotropic glutamate receptor 5 may be involved in macrophage plasticity

Abstract Background Macrophages are a functionally heterogeneous cell population and depending on microenvironments they polarize in two main groups: M1 and M2. Glutamic acid and glutamate receptors may participate in the regulation of macrophage plasticity. To investigate the role of glutamatergic systems in macrophages physiology, we performed the transfection of mGluR5 cDNAs into RAW-264.7 cells. Results Comparative analysis of modified (RAW-mGluR5 macrophages) and non-modified macrophages (RAW-macrophages) has shown that the RAW-mGluR5 macrophages absorbed more glutamate than control cells and the amount of intracellular glutamate correlated with the expression of excitatory amino acid transporters -2 (EAAT-2). Besides, our results have shown that RAW-mGluR5 macrophages expressed a higher level of peroxisome proliferator-activated receptor γ (PPAR-γ) and secreted more IL-10, high mobility group box 1 proteins (HMGB1) and Galectin-3 than control RAW-macrophages. Conclusions We propose that elevation of intracellular glutamate and expression of mGluR5 may initiate the metabolic rearrangement in macrophages that could contribute to the formation of an immunosuppressive phenotype.

Regulation of metabotropic glutamate subtype 7 and 8 receptors in nucleus tractus solitarius in cardiac nociception in rats / 吉林大学学报(医学版)

Objective To explore the role of metabotropic glutamate receptors (mGluRs)group Ⅲ and its subtypes mGluR7 and mGluR8 in nucleus tractus solitarius(NTS)in cardiac-somatic motor reflex (CMR),and to clarify the modulation role of mGluR Ⅲ and its subtypes in NTS in cardiac nociceptoion.Methods 40 SD rats were randomly divided into L-AP4 group,microinjection of mGluRs Ⅲ agonist L-AP4 0.1,1.0,10.0 or 20.0 nmol in NTS;AMN082 group,microinjection of mGluR7 agonist AMN082 1,2 or 4 nmol;DCPG group,microinjection of mGluR8 agonist DCPG 4, 6 or 8 nmol;MSOP group, microinjection of mGluR Ⅲ antagonist MSOP 20 or 100 nmol,20 nmol MSOP+410 nmol L-AP,20 nmol MSOP+2 nmol AMN082,20 nmol MSOP+6 nmol DCPG. The changes of CMR of the rats in various groups were observed.Results Compared with control,the CMR in L-AP4 and AMN082 groups was decreased (P0.05);the CMR in MSOP group after injection of 100 nmol MSOP was increased (P0.05).Conclusion The group Ⅲ mGluRs in the NTS play an inhibitory role in cardiac nociception, and mGluR7 has anti-nociceptive effects while mGluR8 has pro-nociceptive effects.

Intrathecal administration of metabotropic glutamate receptor subtype 5 antagonist on pain behavior and spinal astrocytes activation in mouse mod of bone cancer pain / 中华行为医学与脑科学杂志

Objective To investigate effects of metabotropic glutamate receptor subtype 5 (mGluR5) antagonist MTEP on the nociceptive behavior and the expression of glial fibrillary acidic protein (GFAP) in spinal cord associated with bone cancer pain. Methods C3H/HeNCrlVr 60 male mice were randomly divided into 5 groups: ( 1 ) normal control group: the mice were given food and water ad libitum; ( 2 ) MTEP + Tumor group: the mice were treated by intrathecal gdministration ( once daily on the days 14 ～20 after inoculation of tumor cells)with MTEP (150 nmol); (3) physiological saline + Tumor group:the tumor mice were treated with the same volume of physiological saline; (4) MTEP + Sham group: the sham mice were treated with the same dose of MTEP;(5) physiological saline + Sham group: the sham mice were treated with the same volume of physiological saline.the mice pain behaviors were assessed with the paw withdrawal thermal latency (PWTL) at the corresponding time points, then the mice were killed and the samples of spinal cord were used to real-time PCR and western blot detection of GFAP mRNA and protein expression. Results The basic values of PWTL had no significant differences among all groups (P＜0.05). At day 14 after operation,no significant difference was found in the PWTL value between normal control group and the sham operation group. But in tumor group, the PWTL value was significantly lower than in the normal control group (P＜ 0.05 ). At day 21 after operation,the PWTL and the level of GFAP expression in the spinal cord had no significant differences among normal control group, MTEP + Sham group and physiological saline + Sham group (P ＞ 0.05 ); the PWTL ( (6. 18 ± 1.29 ) s) in physiological saline + Tumor group was significantly lower than in normal control group ( ( 15.91 ± 1.65 )s), physiological saline + Sham group ( ( 16.57 ± 1.86) s) and MTEP + Sham group ( ( 17.05 ± 2.43 ) s) (P ＜ 0.05 ), but the level of GFAP expression was higher than in the above three groups. In MTEP +Tumor group ,the PWTL (9.39 ± 1.94s) was higher than in physiological saline + Tumor group, and the level of GFAP expression was lower than in physiological saline +Tumor group (P ＜ 0.05 ). Conclusion Inhibiting spinal activation of astrocytes may be one of the MTEP anticancer pain mechanisms.

Spinal Metabotropic Glutamate Receptors (mGluRs) are Involved in the Melittin-induced Nociception in Rats

Intraplantar injection of melittin has been known to induce sustained decrease of mechanical threshold and increase of spontaneous flinchings. The present study was undertaken to investigate how the melittin-induced nociceptive responses were modulated by changes of metabotropic glutamate receptor (mGluR) activity. Changes in paw withdrawal threshold (PWT), number of flinchings and paw thickness were measured at a given time point after injection of melittin (10microgram/paw) into the mid-plantar area of rat hindpaw. To observe the effects of mGluRs on the melittin-induced nociceptions, group I mGluR (AIDA, 100microgram and 200microgram), mGluR1 (LY367385, 50microgram and 100microgram) and mGluR5 (MPEP, 200microgram and 300microgram) antagonists, group II (APDC, 100microgram and 200microgram) and III (L-SOP, 100microgram and 200microgram) agonists were intrathecally administered 20 min before melittin injection. Intraplantar injection of melittin induced a sustained decrease of mechanical threshold, spontaneous flinchings and edema. The effects of melittin to reduce mechanical threshold and to induce spontaneous flinchings were significantly suppressed following intrathecal pre-administration of group I mGluR, mGluR1 and mGluR5 antagonists, group II and III mGluR agonists. Group I mGluR antagonists and group II and III mGluR agonists had no significant effect on melittin-induced edema. These experimental findings indicate that multiple spinal mGluRs are involved in the modulation of melittin-induced nociceptive responses.

The Role of Central Group I mGluRs for CFA-induced Knee Joint Pain Model in Rats / 대한마취과학회지

BACKGROUND: Glutamate is the predominant excitatory neurotransmitter in the central and peripheral nervous system and has known to be involved in nociceptive transmission and central sensitization. It acts through ligand gated ionotropic glutamate receptors (iGluRs) and G protein-coupled metabotropic glutamate receptors (mGluRs). And mGlu 1, 5 receptors have been recognized to play a role in nociceptive processing. We want to investigate whether central mGluR1 and mGluR5 antagonists could reverse the behavioral signs of weight bearing and secondary mechanical hyperalgesia induced by chronic knee joint inflammation. METHODS: MGluR1 antagonist, (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA: 25, 50, 100 microM/10 microliter, n = 7 per group) and selective mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP: 25, 100, 200 nM/10 microliter, n = 7 per group) were injected intrathecally 5 days after Complete Freund's Adjuvant (CFA, 150 microliter) injection into knee joint and behavior signs of weight bearing and secondary mechanical hyperalgesia were observed. RESULTS: CFA significantly reduced the magnitude of right hind paw weight bearing and decreased the withdrawal threshold to mechanical stimulation compared to contralateral side. Higher dose of AIDA (100 microM) significantly reversed the reduction of weight bearing, but MPEP did not. AIDA reversed the decrease of the paw withdrawal threshold to mechanical stimulation at the dosage of 50 and 100 microM respectively. MPEP significantly increased the paw withdrawal threshold to mechanical stimulation in a dose dependent manner. CONCLUSIONS: Group I mGluRs were involved in maintenance of primary and secondary mechanical hyperalgesia.

Antinociceptive Effects of Intrathecal Metabotropic Glutamate Receptor Compounds and Morphine in Rats / 대한통증학회지

BACKGROUND: Spinal metabotropic glutamate receptors (mGluRs) and opioid receptors are involved in the modulation of nociception. Although opioid receptors agonists are active for pain, the effects of the compounds for the mGluRs have not been definitely investigated at the spinal level. We examined the effects of the intrathecal mGluR compounds and morphine in the nociceptive test, and then we further clarified the role of the spinal mGluRs. In addition, the nature of the pharmacological interaction after the coadministration of mGluRs compounds with morphine was determined. METHODS: Catheters were inserted into the intrathecal space of male SD rats. For the induction of pain, 50microl of 5% formalin solution or a thermal stimulus was applied to the hindpaw. An isobolographic analysis was used for the evaluation of the drug interaction. RESULTS: Neither group I mGluR compounds nor group III mGluR compounds produced any antinociceptive effect in the formalin test. The group II mGluR agonist (APDC) had little effect on the formalin-induced nociception. The group II mGluR antagonist (LY 341495) caused a dose-dependent suppression of the phase 2 flinching response on the formalin test, but it did not reduce the phase 1 response of the formalin test nor did it increase the withdrawal latency of the thermal stimulus. Isobolographic analysis revealed a synergistic interaction after the intrathecal delivery of a LY 341495-morphine mixture. CONCLUSIONS: These results suggest that group II mGluRs are involved in the facilitated processing at the spinal level, and the combination of LY 341495 with morphine may be useful to manage the facilitated pain state.

The protective effect of LY367385 on impairment of cultured mouse cerebral cortical neurons induced by sodium glutamate or oxygen-glucose deprivation / 中国康复理论与实践

@#ObjectiveTo investigate the protective effect of LY367385 on impairment of cultured mouse cerebral cortical neurons induced by sodium glutamate (Glu) or oxygen-glucose deprivation (OGD).MethodsNeuron damage induced by Glu or OGD, as well as the action of (S)-(+)-a-amino-4-carboxy-2-methylbenzeneacetic acid (LY367385) were measured by determining the leakage of lactate dehydrogenase (LDH) from neurons. Immunocytochemistry and immunofluorescent methods were used to detect the expression of anti-mGluR1α. Morphological observation of primary cortical neurons was performed by phase contrast microscope.ResultsFollowing the exposure to 0.1 mmol/L Glu for 1 h or OGD for 1 h, LDH leakage from neurons obviously increased (P< 0.01 ). 50 mmol/L LY367385, when co-incubated with Glu or OGD, markedly reduced the LDH leakage (P<0.01). The 24-h leakage of LDH was increased from cells exposed to 0.1 mmol/L Glu for 15 min. Pre-and post-treatment with LY367385 (50 mmol/L ) decreased the leakage of LDH. The cultured neurons expressed mGluR1α.ConclusionLY367385 has protective effect on neurons damaged by Glu or OGD. It may be related to antagonizing mGluR1α.

Group Ⅱ and Ⅲ metabotropic glutamate receptors agonists reverse 1-methyl-4-phenylpyridinium-induced glutamate uptake inhibition in C6 glioma cells / 中国临床药理学与治疗学

AIM: To study the effect of group Ⅱ and Ⅲ metabotropic glutamate receptors (mGluRs) agonists on 1-methyl-4-phenylpyridinium (MPP~+)-induced glutamate uptake inhibition in C6 glioma cells. METHODS: The glutamate uptake into astrocytes was measured by using radio-ligand binding assay method. RESULTS: It was shown that Group Ⅱ mGluRs agonist (2' S, 2' R, 3 ' R) -2- (2', 3 ' -dicarboxycyclopropyl) glycine (DCG-Ⅳ) (100 ?mol?L~(-1)) and Group Ⅲ mGluRs agonist L(+)-2-amino-4-phosphonobutyric acid (L-AP4) (100 ?mol?L~(-1)) significantly reversed MPP~+-induced glutamate uptake inhibition. Furthermore, the enhancement effects of DCG-Ⅳ and L-AP4 were blocked by their respective antagonists, (RS)-1 -Amino-5-phosphonoinan-1-carboxylic acid (APICA) and (RS)-?-methylserine-O-phosphate (MSOP). CONCLUSION: Group Ⅱ and Ⅲ mGluRs agonists produce neuroprotective effects by enhancing the activity of glutamate transporters.

Modulation of Amygdala Synaptic Transmission by Metabotropic Glutamate Receptors

Metabotropic glutamate receptors (mGluRs), classified into three groups (group I, II, III), play a critical role in modulation of synaptic transmission at central and peripheral synapses. In the present study, extracellular field potential recording techniques were used to investigate effects of mGluR agonists on excitatory synaptic transmission at thalamic input synapses onto the lateral amygdala. The non-selective mGluR agonist t-ACPD (100 microM) produced reversible, short-term depression, but the group III mGluR agonist L-AP4 (50 microM) did not have any significant effects on amygdala synaptic transmission, suggesting that group I and/or II mGluRs are involved in the modulation by t-ACPD. The group I mGluR agonist DHPG (100 microM) produced reversible inhibition as did t-ACPD. Unexpectedly, the group II mGluR agonist LCCG-1 (10 microM) induced long-term as well as short-term depression. Thus, our data suggest that activation of group I or II mGluRs produces short-term, reversible depression of excitatory synaptic transmission at thalamic input synapses onto the lateral amygdala. Considering the long-term effect upon activation of group II mGluRs, lack of long-term effects upon activation of group I and II mGluRs may indicate a possible cross-talk among different groups of mGluRs.

Metabotropic glutamate receptors and related nervous diseases / 中国药理学通报

Excessive release of glutamic acid plays an important role in the occurring and development of many nervous system diseases.Ionotropic glutamate receptors antagonists are shown to have therapeutic effect in animal models,but their clinical application is limited by their effects of blocking the normal excitatory neurotransmission.However,metabotropic glutamate receptors can suppress the release of glutamic via presynaptic mechanisms,which makes them the new targeting points of certain nervous system disease.This paper reviews the recent research progress of mGluRs in nervous diseases both at home and abroad.

Agonists of group II and III metabotropic glutamate receptors reverse LPS-induced glutamate uptake inhibition in C6 glioma cells / 中国临床药理学与治疗学

AIM: To study whether agonists of group II and III metabotropic glutamate receptors (mGluRs) exert effects on LPS-induced glutamate uptake inhibition in C6 glioma cells. METHODS: The glutamate uptake into C6 glioma cells was measured by uptake of [3H]-D,L-glutamate; and the apoptosis and the viability of C6 glioma cells were investigated by Hoechst33342 and MTT methods, respectively. RESULTS: LPS (4, 6 ?g/mL) inhibited glutamate uptake significantly compared with that in the control group without effect on the apoptosis and viability of C6 glioma cells. Pretreatment of C6 glioma cells with group II and III mGluRs agonists DCG-IV(100 ?mol/L) and L-AP4(100 ?mol/L) reversed LPS-induced glutamate uptake inhibition. These recovery effects were abolished by their respective antagonists APICA and MSOP. CONCLUSION: Activation of group II and III mGluRs recovers LPS-induced glutamate uptake inhibition in C6 glioma cells, suggesting the enhancement of glutamate uptake is involved in neuroprotective roles exerted by group II and III mGluRs agonists.

Group Ⅱ and Ⅲ metabotropic glutamate receptors agonists reverse 1-methyl-4-phenylpyridinium -induced glutamate uptake inhibition / 中国临床药理学与治疗学

AIM: To study the effects of group Ⅱ and Ⅲ metabotropic glutamate receptors (mGluRs) agonists on 1-methyl-4-phenylpyridinium (MPP+) -induced glutamate uptake inhibition. METHODS: The glutamate uptake into astrocytes was measured by using radio-ligand binding assay method,and the viability of astrocytes was investigated by MTT method. RESULTS: It was shown that MPP+(150, 200 ?mol?L -1 ) inhibited glutamate uptake into astrocytes,but produced no effect on the viability of astrocytes,and the inhibition rates were 58.3 % and 70.1 %,respectively. Group Ⅱ mGluRs agonist (2'S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV) ( 0.1 ,1,10, 100 ?mol?L -1 ) and Group Ⅲ mGluRs agonist L(+)-2-amino-4-phosphonobutyric acid (L-AP4) (1,10, 100 ?mol?L -1 ) significantly reversed MPP+-induced glutamate uptake inhibition. CONCLUSION: MPP+ directly inhibits the function of glutamate transporters,and group Ⅱ and Ⅲ mGluRs agonists produce neuroprotective effects by enhancing the activity of glutamate transporters.

Antioxidation of metabotropic glutamate receptors ligand on unilateral substantia nigral 6-hydroxydopamine lesioned rat / 中国药理学通报

AIM To explore the antioxidation of metabotropic glutamate receptors (mGluRs)ligand on rat models of Parkinson disease. METHODS The rat models of Parkinson disease were established by employing 6 hydroxydopamine to lesion unilateral substantia nigral. The serum total antioxidative capability (T AOC), reactive oxygen species (ROS) inhibition competence and content of glotathione (GSH) were measured with chemical colorimetry. RESULTS Compared with control group, serum T AOC and GSH and ROS inhibition competence increased in all treatment groups, mGluRs antagonist (SIB 1893) group, mGluRs agonists (APDC ) group, mGluRs agonists ( L SOP) group and L DOPA group. The effect of APDC was most prominent. CONCLUSION mGluRs antagonist and mGluRs agonists may exert a partial antioxidation effect on unilateral substantia nigral 6 hydroxydopamine lesioned rat and may be beneficial to the body for alleviating the oxdative stress.

The mechanisms of glutamate release in cerebral ischemia / 中国药理学通报

Glutamate is a major excitatory neurotransmitter in the central nervous system(CNS)and plays an important role in neuronal damage induced by cerebral ischemia. Several mechanisms contribute to modulation of glutamate release during cerebral ischemia, such as vesicular release dependent on calcium, release by reversed operation of glutamate transporters, release through swelling-activated anion channel and receptor-modulating release, etc. This review addresses the mechanisms of glutamate release during cerebral ischemia.

EFFECTS OF INTERLEUKIN-1? ON EXPRESSION OF GROUP Ⅱ mGluR2/3 mRNA IN THE HIPPOCAMPUS OF EPILEPTIC RATS INDUCED BY GLUTAMATE / 解剖学报

Objective To explore the relationship between interleukin-1?(IL-1?) and group Ⅱ metabotropic glutamate receptors(mGluR2/3). Methods The rats were randomly divided into five groups:1