Involvement of brain glutamate release in pyrogenic fever.

Whether the glutamate release in the organum vasculosum laminae terminalis (OVLT) is attributable to genesis of a pyrogenic fever is unclear. The lack of information led us to evaluate the changes in glutamate concentrations of OVLT during the fever induced by staphylococcal enterotoxin A (SEA) in unanesthetized rabbits. Both the OVLT concentrations of glutamate and the colonic temperatures were simultaneously monitored during systemic injection of SEA, MK801 (an N-methyl-D-aspartate (NMDA) receptor channel blocker), ketamine (an NMDA receptor channel blocker), or normal saline. The extracellular dialysates in the brain were collected using a microdialysis probe previously placed in the OVLT region. The concentrations of glutamate in the microdialysates were measured by a high-pressure liquid chromatography in combination with a fluorescence detector. Systemic administration of SEA (30 ng x kg(-1) I.V.) increased both the concentrations of glutamate in the OVLT and the colonic temperatures. Glutamate appeared to rise slightly earlier than body temperature. Pretreatment or posttreatment with MK801 or ketamine significantly attenuated the SEA-induced augmenting glutamate release in the OVLT and fever in rabbits. The suppression of glutamate release appeared to start slightly earlier than temperature decline. In addition, the SEA-induced fever could be mimicked by direct injection of glutamate or SEA into the OVLT area. The fever induced by intra-OVLT injection of SEA or glutamate was significantly attenuated by pretreatment with an intra-OVLT dose of MK801 (5 microg) or ketamine (10 microg). The results suggest that glutamatergic pathways in the OVLT region are in pyrogenic fever genesis.     

The diverse roles of vesicular glutamate transporter 3

The expression of vesicular glutamate transporters (VGLUTs) 1 and 2 accounts for the ability of most traditionally accepted excitatory neurons to release glutamate by exocytosis. However, several cell populations (serotonin and dopamine neurons) have been demonstrated to release glutamate in vitro and do not obviously express these transporters. Rather, these neurons express a novel, third isoform that in fact appears confined to neurons generally associated with a transmitter other than glutamate. They include serotonin and possibly dopamine neurons, cholinergic interneurons in the striatum, and GABAergic interneurons of the hippocampus and cortex. Although the physiological role of VGLUT3 remains largely conjectural, several observations in vivo suggest that the glutamate release mediated by VGLUT3 has an important role in synaptic transmission, plasticity, and development.     

The Role of Ionotropic Glutamate Receptors in Childhood Neurodevelopmental Disorders: Autism Spectrum Disorders and Fragile X Syndrome

Autism spectrum disorder (ASD) and Fragile X syndrome (FXS) are relatively common childhood neurodevelopmental disorders with increasing incidence in recent years. They are currently accepted as disorders of the synapse with alterations in different forms of synaptic communication and neuronal network connectivity. The major excitatory neurotransmitter system in brain, the glutamatergic system, is implicated in learning and memory, synaptic plasticity, neuronal development. While much attention is attributed to the role of metabotropic glutamate receptors in ASD and FXS, studies indicate that the ionotropic glutamate receptors (iGluRs) and their regulatory proteins are also altered in several brain regions. Role of iGluRs in the neurobiology of ASD and FXS is supported by a weight of evidence that ranges from human genetics to in vitro cultured neurons. In this review we will discuss clinical, molecular, cellular and functional changes in NMDA, AMPA and kainate receptors and the synaptic proteins that regulate them in the context of ASD and FXS. We will also discuss the significance for the development of translational biomarkers and treatments for the core symptoms of ASD and FXS.     

An electrophysiological study of the action of N-methyl-D-aspartate on excitatory synaptic transmission in the optic tectum of the frog in vitro

Excitatory synaptic field potentials, induced by stimulating optic nerve fibers, were recorded from in vitro preparations of the optic tectum of the frog. Bath-applied N-methyl-D-aspartate (NMDA), glutamate or quisqualate elicited transient enhancement in these field potentials, followed by a sustained depression reversible on washout. Responses to glutamate or quisqualate and the amplitude of control synaptic potentials, were not affected by the NMDA receptor antagonists aminophosphonovalerate (APV), 3(2-carboxypiperazin-4-yl)propyl-1-phosphonate (CPP), ketamine, magnesium ions or dizocipiline (MK 801) which, on the other hand, blocked the effects of NMDA. The antagonist dinitroquinoxaline-2,3-dione (DNQX), which is preferential for non-NMDA receptors, blocked the action of glutamate and synaptic transmission. In the presence of strychnine, glycine reversed the block of NMDA-mediated responses caused by magnesium. It is suggested that in the optic tectum of the frog, glutamate is the excitatory transmitter of at least one class of optic nerve fibers and that it acts through non-NMDA receptors. Although this area of the brain contains a well-developed NMDA receptor system, its function in physiological synaptic transmission remains to be elucidated.     

What Drives The Tonic Activity Of Presympathetic Neurons In The Rostral Ventrolateral Medulla?

1. The present review discusses the mechanisms that maintain the tonic activity of presympathetic cardiovascular neurons in the rostral part of the ventrolateral medulla. 2. Experimental evidence is reviewed that indicates that these neurons receive both tonic excitatory and tonic inhibitory synaptic inputs. The former appear to be mediated, at least in part, by glutamate receptors and the latter appear to be mediated by GABA receptors. 3. There is also evidence that these neurons have the capacity to generate action potentials in the absence of synaptic inputs. However, at present, there is not clear evidence that such an intrinsic pacemaker-like mechanism contributes to the tonic activity of these neurons under normal resting conditions. 4. These neurons are also chemosensitive and this may contribute to their tonic activation under conditions of hypoxia or hypercapnia.     

囊泡谷氨酸转运体与神经系统疾病

囊泡谷氨酸转运体(vesicular glutamate transporters,VGLUTs)能特异地装载谷氨酸进入突触囊泡并促进释放,它包括3个成员,其中VGLUT1和VGLUT2是谷氨酸能神经元和它们轴突末端高度特异的标志,同时VGLUT1标志着皮质-皮质投射,VGLUT2标志着丘脑-皮层投射。而VGLUT3则会出现在胆碱能中间神经元、5-羟色胺能神经元、海马和皮层中GABA能中间神经元中。VGLUTs的异常会导致兴奋性神经递质谷氨酸的异常,从而诱发多种神经系统疾病。该文综述了VGLUTs的功能障碍与阿尔采末病(Alzheimer’sdisease,AD)、帕金森病(Parkinson’s disease,PD)、精神分裂症、抑郁症、癫痫、耳聋发病的关系的研究进展,为这些疾病的防治提供新的线索。     

Synaptic transmission at functionally identified synapses in the enteric nervous system: roles for both ionotropic and metabotropic receptors

Digestion and absorption of nutrients and the secretion and reabsorption of fluid in the gastrointestinal tract are regulated by neurons of the enteric nervous system (ENS), the extensive peripheral nerve network contained within the intestinal wall. The ENS is an important physiological model for the study of neural networks since it is both complex and accessible. At least 20 different neurochemically and functionally distinct classes of enteric neurons have been identified in the guinea pig ileum. These neurons express a wide range of ionotropic and metabotropic receptors. Synaptic potentials mediated by ionotropic receptors such as the nicotinic acetylcholine receptor, P2X purinoceptors and 5-HT(3) receptors are seen in many enteric neurons. However, prominent synaptic potentials mediated by metabotropic receptors, like the P2Y(1) receptor and the NK(1) receptor, are also seen in these neurons. Studies of synaptic transmission between the different neuron classes within the enteric neural pathways have shown that both ionotropic and metabotropic synaptic potentials play major roles at distinct synapses within simple reflex pathways. However, there are still functional synapses at which no known transmitter or receptor has been identified. This review describes the identified roles for both ionotropic and metabotropic neurotransmission at functionally defined synapses within the guinea pig ileum ENS. It is concluded that metabotropic synaptic potentials act as primary transmitters at some synapses. It is suggested identification of the interactions between different synaptic potentials in the production of complex behaviours will require the use of well validated computer models of the enteric neural circuitry.     

Glutamate receptors in glia: new cells, new inputs and new functions

Functional glutamate receptors are expressed on the majority of glial cell types in the developing and mature brain. Although glutamate receptors on glia are activated by glutamate released from neurons, their physiological role remains largely unknown. Potential roles for these receptors in glia include regulation of proliferation and differentiation, and modulation of synaptic efficacy. Recent anatomical and functional evidence indicates that glutamate receptors on immature glia are activated through direct synaptic inputs. Therefore, glutamate and its receptors appear to be involved in a continuous crosstalk between neurons and glia during development and also in the mature brain.     

AGE-RELATED SYNAPTIC CHANGES IN THE CA1 STRATUM RADIATUM AND SPATIAL LEARNING IMPAIRMENT IN RATS

• 1 Age‐related impairments in hippocampus‐dependent spatial learning and memory are not associated with a loss of neurons, but may be related to synaptic changes. In the present study, we analysed the behavioural performance of adult, middle‐aged and old Wistar rats using the Morris water maze, as well as the structure of synapses and the expression of autophosphorylated Ca²⁺/calmodulin‐dependent protein kinase II at threonine 286 (pThr286‐αCaMKII), a key post‐synaptic protein in the CA1 stratum radiatum, in the same rats.
• 2 Old Wistar rats showed significant cognitive deficits. Synaptic density, the area of post‐synaptic densities and the total number of synapses in the CA1 stratum radiatum of old rats were significantly decreased compared with adult rats. The decrease in autophosphorylated pThr286‐αCaMKII was age dependent.
• 3 These findings reveal that age‐related impairments in learning and memory are associated with synaptic atrophy. The decreased expression of pThr286‐CaMKII may result in reduced synaptic function with ageing.

     

Cyclooxygenase inhibitors attenuate augmented glutamate release in organum vasculosum laminae terminalis and fever induced by staphylococcal enterotoxin A

Both the hyperthermia and augmented glutamate release in the organum vasculosum laminae terminalis (OVLT) after an intravenous dose (30 ng/kg) of staphylococcal enterotoxin A (SEA) were significantly reduced by pretreatment with intravenous administration of cyclooxygenase inhibitors such as aspirin (1 - 10 mg/kg), sodium salicylate (1 - 10 mg/kg), or diclofenac (10 mg/kg). Intra-OVLT administration of 50 - 200 microg in 1.0 microl of either aspirin or sodium salicylate 60 min before or 120 min after an intra-OVLT dose (50 microg in 1.0 microl) of glutamate also significantly suppressed the glutamate-induced hyperthermia. These findings suggest that inhibition of cyclooxygenase receptor mechanisms suppresses SEA fever by inhibition of glutamate release in the OVLT of rabbit brain.     

SKF97541抑制大鼠骶髓后联合核神经元

目的研究GABAB受体特异性激动剂SKF97541对骶髓后联合核(SDCN)神经元的作用。方法在大鼠骶段脊髓横切薄片上,利用全细胞膜片钳法记录骶髓后联合核神经元。电流钳记录模式下,观察SKF97541对神经元膜电位和动作电位发放的影响。电压钳模式下,观察谷氨酸能兴奋性突触后电流(EPSCs)对SKF97541处理的变化。结果SKF97541(0.5μmol.L-1)通过作用于GABAB受体,减少SDCN神经元动作电位发放,同时促进细胞膜超极化。SKF97541在电压钳模式下,减少谷氨酸介导的微小EPSCs的频率,但对振幅无影响,提示SKF97541通过作用于突触前GABAB受体抑制谷氨酸释放。突触前刺激引起的突触后电位,也被SKF97541抑制。结论在骶髓后联合核,SKF97541通过作用于突触后GABAB受体,直接抑制神经元的兴奋性和动作电位发放;并通过突触前GABAB受体,抑制谷氨酸的释放。以上结果提示SKF97541的抑制作用可能抑制骶髓后联合核神经元对伤害性信息的传递。     

The PDZ domains of mLin-10 regulate its trans-Golgi network targeting and the surface expression of AMPA receptors

Dynamic regulation of synaptic AMPA receptor localization underlies certain forms of synaptic plasticity and researchers are just beginning to identify molecules that may play a role in the synaptic delivery of glutamate receptors. One candidate is mLin-10, the mammalian homolog of the C. elegans receptor targeting protein LIN-10. Here, we investigated the role of mLin-10 in glutamate receptor trafficking. Cellular localization studies, in both whole brain and cultured neurons, revealed that mLin-10 is enriched in the trans-Golgi network and present in dendrites and spines--regions where protein sorting and synaptic delivery are known to occur. The specific localization of mLin-10 in Golgi is disrupted by a point mutation in an mLin-10 PDZ domain, indicating that a PDZ domain mediates this localization. Interactions between mLin-10 and glutamate receptors in both intracellular and synaptic membrane fractions were detected through biochemical assays. GST-pull down and co-immunoprecipitation experiments in heterologous cells delineated the protein domains required for interaction. These results demonstrated that glutamate receptors interact directly with mLin-10 through a PDZ domain-mediated mechanism. A PDZ point mutation enhances surface delivery of exogenous glutamate receptors in transfected neurons, suggesting that mLin-10 may regulate AMPA receptor trafficking in vivo.     

Glutamatergic neural transmission in the nucleus tractus solitarius: N-methyl-D-aspartate receptors

1. The nucleus tractus solitarius (NTS) is the first central site where the reflex control of autonomic, including baroreceptor, reflex function is coordinated. Autonomic signals are transmitted from the first-order visceral afferent fibres to second-order NTS neurons by L-glutamate. It is well established that activation of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptors, which mediate the fast component of L-glutamate signalling, is required for generating changes in membrane potentials of the second-order NTS neurons. The contribution of the slower-developing, longer-lasting N-methyl-D-aspartate (NMDA) receptor-mediated component of glutamate signalling to synaptic transmission at these synapses is less well understood. 2. The aim of this work is to highlight evidence that functional NMDA receptors exist on second-order NTS neurons in autonomic, including baroreceptor, afferent pathways by determining whether NMDA receptors can be activated by: (i) exogenous application of NMDA; and (ii) endogenous release of L-glutamate from autonomic afferent fibres. Studies were performed on second-order neurons in transverse and horizontal brainstem slices containing the intermediate NTS and the tractus solitarius. Second-order NTS neurons were identified by electrophysiological criteria or by attached fluorescent-labelled aortic depressor nerve (ADN) boutons. 3. N-Methyl-D-aspartate (50 nmol(-2) micromol) dose-dependently evoked excitatory post-synaptic currents in second-order NTS neurons (P = 0.004; n = 4). The NMDA receptor-mediated currents were also synaptically evoked by low-frequency stimulation of the autonomic afferent fibres in the tractus solitarius. The NMDA receptor-mediated currents were blocked by the NMDA receptor antagonist AP5 (n = 7; P = 0.027). 4. The findings suggest that functional NMDA receptors exist on second-order NTS neurons. While the NMDA receptor- mediated currents may not be required for signal transmission when the second-order neurons are at resting membrane potential, their activation may help to modulate autonomic signal transmission in the NTS under conditions in which the membrane is depolarized by high frequency or convergent inputs.     

Inhibition of tetanically sciatic stimulation-induced LTP of spinal neurons and Fos expression by disrupting glutamate transporter GLT-1

Tetanic stimulation of the sciatic nerve produces spinal long-term potentiation (LTP) of C-fiber evoked field potentials, which is NMDA dependent and may be the substrate of inflammation- or nerve injury-produced central sensitization. Glial glutamate transporter GLT-1 has been considered as an important regulator of excitatory synaptic transmission and nociception. In the present study, we investigated the effects of GLT-1 on the spinal LTP and Fos expression induced by tetanically sciatic stimulation. Intrathecal administration of dihydrokainate (DHK), a GLT-1 selective inhibitor, partially inhibited (0.1 mM) or completely blocked (3.0 mM) the spinal LTP, which may be related to an accumulation of extracellular glutamate. Intrathecal DHK (3.0 mM) also suppressed tetanic stimulation-induced spinal Fos expression. Double immunofluorescence showed no Fos expression in glial fibrillary acidic protein (GFAP)-positive cells, and the cell DNA fragment study failed to detect a significant apoptosis of spinal neurons. These results suggest that disruption of GLT-1 may be associated with the inhibition of functional activation of spinal neurons expressing Fos, but not with glutamate excitotoxicity. In conclusion, glial GLT-1 may play an important role in tetanically sciatic stimulation-induced LTP of spinal nociceptive neurons via the regulation of extracellular levels of glutamate to an appropriate concentration.     

Role of GABA receptors in nitric oxide inhibition of dorsolateral periaqueductal gray neurons

Nitric oxide (NO) affects neuronal activity of the midbrain periaqueductal gray (PAG). The purpose of this report was to investigate the role of GABA receptors in NO modulation of neuronal activity through inhibitory and excitatory synaptic inputs within the dorsolateral PAG (dl-PAG). First, spontaneous miniature inhibitory postsynaptic currents (mIPSCs) and excitatory postsynaptic currents (mEPSCs) were recorded using whole cell voltage-clamp methods. Increased NO by either S-nitroso-N-acetyl-penicillamine (SNAP, 100 microM) or L-arginine (50 microM) significantly augmented the frequency of mIPSCs of the dl-PAG neurons without altering their amplitudes or decay time constants. The effects were eliminated after bath application of carboxy-PTIO (NO scavenger), and 1-(2-trifluorom-ethylphenyl) imidazole (NO synthase inhibitor). In contrast, SNAP and L-arginine did not alter mEPSCs in dl-PAG neurons. However the frequency of mEPSCs was significantly increased with prior application of the GABA(B) receptors antagonist, CGP55845. In addition, NO significantly decreased the discharge rate of spontaneous action potentials in the dl-PAG neurons and the effect was reduced in the presence of the GABA(A) receptor antagonist, bicuculline. Our data show that within the dl-PAG NO potentiates the synaptic release of GABA, while NO-induced GABA presynaptically inhibits glutamate release through GABA(B) receptors. Overall, NO suppresses neuronal activity of the dl-PAG via a potentiation of GABAergic synaptic inputs and via GABA(A) receptors.     

The effects of iontophoretically applied antagonists on auditory nerve and amino acid evoked excitation of anteroventral cochlear nucleus neurons

Experiments were conducted on cats to compare the actions of glutamate diethylester (GDEE) with d-α-aminoadipate (DAA), dl-α-aminosuberate (DLAS), HA-966 and magnesium (Mg) ions on glutamate, aspartate and $\text{N-}\text{methyl}\text{-}\text{d}\text{-}\text{aspartate}$ (NMDA)-induced excitation of anteroventral cochlear nucleus neurons and on the synaptic excitation by the auditory nerve. The purpose of the study was to characterize further the postsynaptic receptor and synaptic transmitter. GDEE consistently depressed glutamate, more than aspartate responses and had little if any effect on NMDA responses and synaptic transmission. The responses to NMDA and aspartate were particularly sensitive to DAA, DLAS and Mg ions. The synaptically evoked response was also sensitive to DAA, DLAS and Mg ions as well as HA-966. The results indicate that the synaptic receptor is of the NMDA type. Although a transmitter role for glutamate in a folded configuration is not ruled out, the preferential interaction of aspartate with the synaptic receptor suggests that aspartate is more likely to be the transmitter in the auditory nerve.     

Treatment of hippocampal neurons with cyclosporin A results in calcium overload and apoptosis which are independent on NMDA receptor activation

Calcineurin is a ubiquitous calcium/calmodulin dependent protein phosphatase that has been shown to regulate the activity of ion channels, glutamate release, and synaptic plasticity. In the present study we show that CsA, a specific inhibitor of calcineurin, affects the survival of cultures developed from hippocampal dentate gyrus. Mixed neuronal-glial cultures exposed to 8 - 40 microM CsA undergo cell death characterized by apoptotic changes in cellular and nuclear morphology. TUNEL-positive staining was observed only in neurons that developed pyknotic morphology after treatment with 8 microM CsA for 24 - 72 h. Immunocytochemical staining with an anti-GFAP monoclonal antibody revealed that astrocytes from mixed neuronal/glial cultures were unaffected by exposure to CsA at doses toxic for neurons and all TUNEL-positive cells were neurons. MK-801, a noncompetitive inhibitor of glutamate receptor, does not inhibit the appearance of TUNEL-positive neurons and apoptotic changes in nuclear morphology. Preincubation of cells with 8 microM CsA increased basal intracellular calcium level in time dependent manner and decreased relative calcium response to glutamate. Application of 1 microM MK-801 had no effect on CsA-induced changes in Ca(2+) level. Our findings suggest that the neuronal death after CsA treatment is not a result of glutamate excitotoxicity and the increase in intracellular calcium concentration in neurons is not dependent on calcium influx via NMDA channel.     

γ-Hydroxybutyrate inhibits excitatory postsynaptic potentials in rat hippocampal slices

γ-Hydroxybutyrate (GHB) has been shown to mimic different central actions of ethanol, to suppress alcohol withdrawal syndrome, and to reduce alcohol consumption both in rats and in humans. The aim of the present study was to determine if GHB shared with alcohol the ability to inhibit glutamate action at both NMDA and AMPA/kainate receptors. The NMDA or the AMPA/kainate receptors-mediated postsynaptic potentials were evoked in CA1 pyramidal neurons by stimulation of Schaffer-collateral commissural fibers in the presence of CGP 35348, bicuculline to block the GABA_B and GABA_A receptors, and 10 μM 6,7-dinitroquinoxaline-2,3-dione (DNQX) or 30 μM -2-amino-5-phosphonovalerate (d-APV) to block AMPA/kainate or NMDA receptors, respectively. GHB (600 μM) produced a depression of both NMDA and AMPA/kainate receptors-mediated excitatory postsynaptic potentials with recovery on washout. The GHB receptors antagonist, NCS-382, at the concentration of 500 μM had no effect per se on these responses but prevented the depressant effect of GHB (600 μM) on the NMDA and AMPA/kainate-mediated responses. In the paired-pulse experiments, GHB (600 μM) depressed the amplitude of the first and the second evoked AMPA/kainate excitatory postsynaptic potentials, and significantly increased the paired-pulse facilitation (PPF). These results suggest that GHB inhibits excitatory synaptic transmission at Schaffer-collateral commissural–pyramidal neurons synapses by decreasing the probability of release of glutamate.     

In vivo knockdown of astroglial glutamate transporters GLT-1 and GLAST increases excitatory neurotransmission in mouse infralimbic cortex: Relevance for depressive-like phenotypes

Alterations of energy metabolism and of astrocyte number/function in ventral anterior cingulate cortex (vACC) have been reported in major depressive disorder (MDD) patients and may contribute to MDD pathophysiology. We recently developed a mouse model of MDD mimicking these alterations. We knocked down the astroglial glutamate transporters GLAST and GLT-1 in infralimbic cortex (IL, rodent equivalent of vACC) using small interfering RNA (siRNA). GLAST and GLT-1 siRNA microinfusion in IL evoked a depressive-like phenotype, associated with a reduced serotonergic function and reduced forebrain BDNF expression. Neither effect occurred after siRNA application in the adjacent prelimbic cortex (PrL), thus emphasizing the critical role of vACC/IL in MDD pathogenesis. Here we examined the cellular/network basis of the changes induced in IL using intracellular recordings of layer V pyramidal neurons from mice microinjected with siRNA 24 h before. We analyzed (i) the electrophysiological characteristics of neurons; (ii) the synaptic transmission properties, by monitoring miniature, spontaneous and evoked EPSCs, and (iii) the gliotransmission, by monitoring slow inward currents (SICs), mediated by astrocytic glutamate release and activation of extra-synaptic NMDA receptors. GLT-1 and GLAST knockdown led to a more depolarized membrane potential and increased action potential firing rate of layer V pyramidal neurons, and enhanced excitatory synaptic transmission, as shown by the enhanced amplitude/frequency of spontaneous EPSCs. Gliotransmission was also increased, as indicated by the enhanced SIC amplitude/frequency. Hence, the depressive-like phenotype is associated with IL hyperactivity, likely leading to an excessive top-down inhibitory control of serotonergic activity through IL-midbrain descending pathways.     

Disinhibition of spinal responses to primary afferent input by antagonism at GABA receptors in urethane-anaesthetised rats is dependent on NMDA and metabotropic glutamate receptors

Disruption of spinal GABAergic circuits, which regulate the conveyance of sensory information to spinal cord neurones from the primary afferent system, leads to miscoding of afferent input and often results in hyperresponsiveness states. In the present work, extracellular field potentials elicited by electrical peripheral nerve activation were recorded in the urethane-anaesthetised rat following spinal administration of GABA(A) or GABA(B) receptor-antagonists, and the involvement of glutamate receptors of the NMDA and metabotropic types in changes induced by altered GABAergic function was examined by pre-treating the spinal dorsal horn with appropriate antagonist drugs. Spinal administration of the GABA(A) receptor antagonist bicuculline (BIC) dose-dependently augmented poly- but not monosynaptic field potentials elicited by activation of A fibres or potentials elicited by activation of C fibres, whereas application of the GABA(B) receptor antagonist CGP35348 significantly increased the amplitudes of C- but not A fibre-evoked potentials. BIC-induced augmentation was blocked by pre-treatment with the NMDA receptor antagonist D-(-)-2-amino-5-phosphonopentanoic acid (D-AP5) or the group I or II metabotropic glutamate receptor (mGluR)-antagonists (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA) or (2S)-alpha-ethylglutamic acid (EGLU), respectively, but not by the group III mGluR-antagonist (RS)-alpha-methylserine-O-phosphate (MSOP). Augmentation of spinal field potentials induced by CGP35348 was prevented by pre-treatment with D-AP5 but not with mGluR-antagonists. The present findings provide novel evidence that disparate synaptic mechanisms subserved by metabotropic and NMDA glutamate receptors may be involved in spinal hyperresponsiveness states secondary to decreased GABA(A) or GABA(B) receptor activity.