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mGlu2 metabotropic glutamate receptors restrain inflammatory pain and mediate the analgesic activity of dual mGlu2/mGlu3 receptor agonists
Magda Zammataro, Santina Chiechio, Michael C Montana, Anna Traficante, Agata Copani, Ferdinando Nicoletti, Robert W Gereau
Molecular Pain , 2011, DOI: 10.1186/1744-8069-7-6
Abstract: In this study we used mGlu2 or mGlu3 knock-out mice to dissect the specific role for these two receptors in the endogenous control of inflammatory pain and their specific contribution to the analgesic activity of mixed mGlu2/3 receptor agonists.Our results showed that mGlu2-/- mice display a significantly greater pain response compared to their wild type littermates. Interestingly the increased pain sensitivity in mGlu2-/- mice occurred only in the second phase of the formalin test. No differences were observed in the first phase. In contrast, mGlu3-/- mice did not significantly differ from their wild type littermates in either phase of the formalin test.When systemically injected, a single administration of the mGlu2/3 agonist, LY379268 (3 mg/kg, ip), showed a significant reduction of both phases in wild-type mice and in mGlu3-/- but not in mGlu2-/- mice. However tolerance to the analgesic effect of LY379268 (3 mg/kg, ip) in mGlu3-/- mice developed following 5 consecutive days of injection.Taken together, these results demonstrate that: (i) mGlu2 receptors play a predominant role over mGlu3 receptors in the control of inflammatory pain in mice; (ii) the analgesic activity of mixed mGlu2/3 agonists is entirely mediated by the activation of the mGlu2 subtype and (iii) the development of tolerance to the analgesic effect of mGlu2/3 agonists develops despite the lack of mGlu3 receptors.Metabotropic glutamate (mGlu) receptors are considered promising targets in the treatment of chronic pain. All mGlu receptor subtypes (mGlu1-8), except mGlu6, are widely distributed along the pain neuraxis, and modulate cellular mechanisms of nociceptive sensitization that underlie the development of chronic pain [1-3]. We and others have focused on the role of group-II mGlu receptors (mGlu2 and mGlu3), which are coupled to Gi proteins and depress pain transmission at synapses between primary afferent fibers and second order sensory neurons in the dorsal horn of the spinal cord [4,5]. mG
Metabotropic glutamate receptors inhibit microglial glutamate release  [cached]
Stephen M McMullan,Bounleut Phanavanh,Gary Guo Li,Steven W Barger
ASN Neuro , 2012, DOI: 10.1042/an20120044
Abstract: Pro-inflammatory stimuli evoke an export of glutamate from microglia that is sufficient to contribute to excitotoxicity in neighbouring neurons. Since microglia also express various glutamate receptors themselves, we were interested in the potential feedback of glutamate on this system. Several agonists of mGluRs (metabotropic glutamate receptors) were applied to primary rat microglia, and the export of glutamate into their culture medium was evoked by LPS (lipopolysaccharide). Agonists of group-II and -III mGluR ACPD [(1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid] and L-AP4 [L-(+)-2-amino-4-phosphonobutyric acid] were both capable of completely blocking the glutamate export without interfering with the production of NO (nitric oxide); the group-I agonist tADA (trans-azetidine-2,4-dicarboxylic acid) was ineffective. Consistent with the possibility of feedback, inhibition of mGluR by MSPG [(R,S)-α-2-methyl-4sulfonophenylglycine] potentiated glutamate export. As the group-II and -III mGluR are coupled to Gαi-containing G-proteins and the inhibition of adenylate cyclase, we explored the role of cAMP in this effect. Inhibition of cAMP-dependent protein kinase [also known as protein kinase A (PKA)] by H89 mimicked the effect of ACPD, and the mGluR agonist had its actions reversed by artificially sustaining cAMP through the PDE (phosphodiesterase) inhibitor IBMX (isobutylmethylxanthine) or the cAMP mimetic dbcAMP (dibutyryl cAMP). These data indicate that mGluR activation attenuates a potentially neurotoxic export of glutamate from activated microglia and implicate cAMP as a contributor to this aspect of microglial action.
Metabotropic Glutamate Receptors for Parkinson's Disease Therapy  [PDF]
Fabrizio Gasparini,Thérèse Di Paolo,Baltazar Gomez-Mancilla
Parkinson's Disease , 2013, DOI: 10.1155/2013/196028
Abstract: Excessive glutamatergic signalling within the basal ganglia is implicated in the progression of Parkinson’s disease (PD) and inthe emergence of dyskinesia associated with long-term treatment with L-DOPA. There is considerable research focus on the discovery and development of compounds that modulate glutamatergic signalling via glutamate receptors, as treatments for PD and L-DOPA-induced dyskinesia (LID). Although initial preclinical studies with ionotropic glutamate receptor antagonists showed antiparkinsonian and antidyskinetic activity, their clinical use was limited due to psychiatric adverse effects, with the exception of amantadine, a weak N-methyl-d-aspartate (NMDA) antagonist, currently used to reduce dyskinesia in PD patients. Metabotropic receptor (mGlu receptor) modulators were considered to have a more favourable side-effect profile, and several agents have been studied in preclinical models of PD. The most promising results have been seen clinically with selective antagonists of mGlu5 receptor and preclinically with selective positive allosteric modulators of mGlu4 receptor. The growing understanding of glutamate receptor crosstalk also raises the possibility of more precise modulation of glutamatergic transmission, which may lead to the development of more effective agents for PD. 1. Introduction Parkinson’s disease (PD) is a chronic progressive neurodegenerative disorder of the central nervous system (CNS), characterised by a gradual loss of dopaminergic neurotransmission. Cardinal symptoms of PD include tremor, bradykinesia, and rigidity. Levodopa (L-DOPA) is considered the standard of care for providing symptomatic relief in PD [1]. However, long-term L-DOPA treatment leads to the appearance of motor complications in the majority of responding patients and severely affects their quality of life [2]. After 9 years of L-DOPA treatment, ~90% of PD patients experience dyskinesia [3]. The dyskinesia that develops is often a combination of choreic and dystonic abnormal involuntary movements, collectively termed L-DOPA-induced dyskinesia (PD-LID). Once PD-LID is established, increasing the L-DOPA dose typically worsens dyskinesia and this may prevent the use of L-DOPA at optimal doses required to control motor fluctuations. There are currently no licensed therapies for the treatment of PD-LID, although a number of clinical strategies are employed including adding dopamine agonists, monoamine oxidase inhibitors, adenosine (2A) receptor antagonists, catechol-O-methyl transferase inhibitors, and anticholinergic drugs as part of a L-DOPA-sparing
Glutamate-induced swelling of cultured astrocytes is mediated by metabotropic glutamate receptor
YUAN Fang,WANG Tianyou,

中国科学C辑(英文版) , 1996,
Abstract: The effects of glutamate and its agonists and antagonists on the swelling of cultured astrocytes were studied. Swelling of astrocytes was measured by 3H]-O-methyl-D-glucose uptake. Glutamate at 0.5, 1 and 10mmol/L and irons-l-aminocyclopentane-1,3-dicarboxylic acid (trans-ACPD), a metabotropic glutamate receptor (mGluR) agonist, at 1 mmol/L caused a significant increase in astrocytic volume, whereas alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) was not effective. L-2-amino-3-phosphonopropionic acid (L-AP3), an antagonist of mGluR, blocked the astrocytic swelling induced by trans-ACPD or glutamate. In Ca2+-free condition, glutamate was no longer effective. Swelling of astrocytes induced by glutamate was not blocked by CdCl2 at 20 μmol/L, but significantly reduced by CdCl2 at 300 μmol/L and dantrolene at 30 μmol/L. These findings indicate that mGluR activation results in astrocytic swelling and both extracellular calcium and internal calcium stores play important roles in the genesis of astrocytic swelling induced by glutamate.
Therapeutic Promise and Principles: Metabotropic Glutamate Receptors  [PDF]
Kenneth Maiese,Zhao Zhong Chong,Yan Chen Shang,Jinling Hou
Oxidative Medicine and Cellular Longevity , 2008, DOI: 10.4161/oxim.1.1.6842
Abstract: For a number of disease entities, oxidative stress becomes a significant factor in the etiology and progression of cell dysfunction and injury. Therapeutic strategies that can identify novel signal transduction pathways to ameliorate the toxic effects of oxidative stress may lead to new avenues of treatment for a spectrum of disorders that include diabetes, Alzheimer's disease, Parkinson's disease and immune system dysfunction. In this respect, metabotropic glutamate receptors (mGluRs) may offer exciting prospects for several disorders since these receptors can limit or prevent apoptotic cell injury as well as impact upon cellular development and function. Yet the role of mGluRs is complex in nature and may require specific mGluR modulation for a particular disease entity to maximize clinical efficacy and limit potential disability. Here we discuss the potential clinical translation of mGluRs and highlight the role of novel signal transduction pathways in the metabotropic glutamate system that may be vital for the clinical utility of mGluRs.
N-Acetyl-cysteine causes analgesia by reinforcing the endogenous activation of type-2 metabotropic glutamate receptors  [cached]
Bernabucci Matteo,Notartomaso Serena,Zappulla Cristina,Fazio Francesco
Molecular Pain , 2012, DOI: 10.1186/1744-8069-8-77
Abstract: Background Pharmacological activation of type-2 metabotropic glutamate receptors (mGlu2 receptors) causes analgesia in experimental models of inflammatory and neuropathic pain. Presynaptic mGlu2 receptors are activated by the glutamate released from astrocytes by means of the cystine/glutamate antiporter (System xc- or Sxc-). We examined the analgesic activity of the Sxc- activator, N-acetyl-cysteine (NAC), in mice developing inflammatory or neuropathic pain. Results A single injection of NAC (100 mg/kg, i.p.) reduced nocifensive behavior in the second phase of the formalin test. NAC-induced analgesia was abrogated by the Sxc- inhibitor, sulphasalazine (8 mg/kg, i.p.) or by the mGlu2/3 receptor antagonist, LY341495 (1 mg/kg, i.p.). NAC still caused analgesia in mGlu3 / mice, but was inactive in mGlu2 / mice. In wild-type mice, NAC retained the analgesic activity in the formalin test when injected daily for 7 days, indicating the lack of tolerance. Both single and repeated injections of NAC also caused analgesia in the complete Freund’s adjuvant (CFA) model of chronic inflammatory pain, and, again, analgesia was abolished by LY341495. Data obtained in mice developing neuropathic pain in response to chronic constriction injury (CCI) of the sciatic nerve were divergent. In this model, a single injection of NAC caused analgesia that was reversed by LY341495, whereas repeated injections of NAC were ineffective. Thus, tolerance to NAC-induced analgesia developed in the CCI model, but not in models of inflammatory pain. The CFA and CCI models differed with respect to the expression levels of xCT (the catalytic subunit of Sxc-) and activator of G-protein signaling type-3 (AGS3) in the dorsal portion of the lumbar spinal cord. CFA-treated mice showed no change in either protein, whereas CCI mice showed an ipislateral reduction in xCT levels and a bilateral increase in AGS3 levels in the spinal cord. Conclusions These data demonstrate that pharmacological activation of Sxc- causes analgesia by reinforcing the endogenous activation of mGlu2 receptors. NAC has an excellent profile of safety and tolerability when clinically used as a mucolytic agent or in the management of acetaminophen overdose. Thus, our data encourage the use of NAC for the experimental treatment of inflammatory pain in humans.
Novel Expression Patterns of Metabotropic Glutamate Receptor 6 in the Zebrafish Nervous System  [PDF]
Ying-Yu Huang, Marion F. Haug, Matthias Gesemann, Stephan C. F. Neuhauss
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0035256
Abstract: The metabotropic glutamate receptor 6 (mGluR6 or GRM6) belongs to the class III of the metabotropic glutamate receptor family. It is the only known mGluR that mediates direct synaptic transmission in the nervous system and is thought to mediate the ON-response in the ON-pathway of the vertebrate retina. Phylogenetic and gene structure analysis indicated that the zebrafish genome harbours two mglur6 paralogs, mglur6a and mglur6b. Besides expression in the inner nuclear layer and distinct regions in the brain, both mglur6 paralogs are expressed in ganglion cells of the retina, an expression pattern which can also be observed in the downstream effector molecules gnaoa and gnaob. This unexpected expression pattern is consistent with immunohistological labeling using a peptide antibody specific for the mGluR6b paralog. These expression patterns contradict the existing view that mGluR6 is solely located on ON-bipolar cells where it functions in signal transmission. Consistent with expression in ON-bipolar cells, we report a decreased b-wave amplitude in the electroretinogram after morpholino-based downregulation of mGluR6b, showing a function in the ON response. Our data suggest more widespread functions of mGluR6 mediated signaling in the central nervous system, possibly including sign reversing synapses in the inner retina.
Both Neurons and Astrocytes Exhibited Tetrodotoxin-Resistant Metabotropic Glutamate Receptor-Dependent Spontaneous Slow Ca2+ Oscillations in Striatum  [PDF]
Atsushi Tamura, Naohiro Yamada, Yuichi Yaguchi, Yoshio Machida, Issei Mori, Makoto Osanai
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0085351
Abstract: The striatum plays an important role in linking cortical activity to basal ganglia outputs. Group I metabotropic glutamate receptors (mGluRs) are densely expressed in the medium spiny projection neurons and may be a therapeutic target for Parkinson's disease. The group I mGluRs are known to modulate the intracellular Ca2+ signaling. To characterize Ca2+ signaling in striatal cells, spontaneous cytoplasmic Ca2+ transients were examined in acute slice preparations from transgenic mice expressing green fluorescent protein (GFP) in the astrocytes. In both the GFP-negative cells (putative-neurons) and astrocytes of the striatum, spontaneous slow and long-lasting intracellular Ca2+ transients (referred to as slow Ca2+ oscillations), which lasted up to approximately 200 s, were found. Neither the inhibition of action potentials nor ionotropic glutamate receptors blocked the slow Ca2+ oscillation. Depletion of the intracellular Ca2+ store and the blockade of inositol 1,4,5-trisphosphate receptors greatly reduced the transient rate of the slow Ca2+ oscillation, and the application of an antagonist against mGluR5 also blocked the slow Ca2+ oscillation in both putative-neurons and astrocytes. Thus, the mGluR5-inositol 1,4,5-trisphosphate signal cascade is the primary contributor to the slow Ca2+ oscillation in both putative-neurons and astrocytes. The slow Ca2+ oscillation features multicellular synchrony, and both putative-neurons and astrocytes participate in the synchronous activity. Therefore, the mGluR5-dependent slow Ca2+ oscillation may involve in the neuron-glia interaction in the striatum.
Metabotropic glutamate receptors and their ligands applications in neurological and psychiatric disorders
Ali Shahraki
Physiology and Pharmacology , 2011,
Abstract: Metabotropic glutamate receptors (mGluRs) consist of a large family of G-protein coupled receptors that are critical for regulating normal neuronal function in the central nervous system. The wide distribution and diverse physiological roles of various mGluR subtypes make them highly attractive targets for the treatment of a number of neurological and psychiatric disorders. The discovery of subtype selective ligands for these receptors has provided the tools to support a number of preclinical studies, suggesting the numerous therapeutic potential that lies in the ability selectively to modulate a specific mGluR subtype. mGluRs do not activate ion channels directly but instead through G-protiens activate second messenger mechanisms in the neurons. So far 8 subtypes of mGluRs have been identified which divided into three groups (Group I, II, and III) according to their sequence similarities, Signal transduction mechanisms and pharmacological properties. Depending on the receptor subtype, they might be localized at presynaptic or postsynaptic sites which regulate glutamate and other neurotransmitters release. As I applied many mGluR ligands on hippocampal slices and observed interesting results on synaptic transmission and modulation of certain neurotransmitters such as adenosine, I intended to study their application in neurological diseases. The method was based on my experiences from researches and different seminars to evaluate last decade development on mGluRs and their ligands application in certain neurological disorders. Therefore, aim of this review article is to describe mGluRs and their role in the excitotoxicity and neuroprotection. Then, application of different mGluR ligands for the treatment of a variety of neurological disorders including schizophrenia, Parkinson's disease, anxiety disorders, epilepsy, and drug abuse has been described.
Metabotropic Glutamate Receptors as Novel Therapeutic Targets on Visceral Sensory Pathways  [PDF]
L. Ashley Blackshaw,Amanda J. Page,Richard L. Young
Frontiers in Neuroscience , 2011, DOI: 10.3389/fnins.2011.00040
Abstract: Metabotropic glutamate receptors (mGluR) have a diverse range of structures and molecular coupling mechanisms. There are eight mGluR subtypes divided into three major groups. Group I (mGluR1 and 5) is excitatory; groups II (mGluR2 and 3) and III (mGluR 4, 6, and 7) are inhibitory. All mGluR are found in the mammalian nervous system but some are absent from sensory neurons. The focus here is on mGluR in sensory pathways from the viscera, where they have been explored as therapeutic targets. Group I mGluR are activated by endogenous glutamate or constitutively active without agonist. Constitutive activity can be exploited by inverse agonists to reduce neuronal excitability without synaptic input. This is promising for reducing activation of nociceptive afferents and pain using mGluR5 negative allosteric modulators. Many inhibitory mGluR are also expressed in visceral afferents, many of which markedly reduce excitability. Their role in visceral pain remains to be determined, but they have shown promise in inhibition of the triggering of gastro-esophageal reflux, via an action on mechanosensory gastric afferents. The extent of reflux inhibition is limited, however, and may not reach a clinically useful level. On the other hand, negative modulation of mGluR5 has very potent actions on reflux inhibition, which has produced the most likely candidates so far as therapeutic drugs. These act probably outside the central nervous system, and may therefore provide a generous therapeutic window. There are many unanswered questions about mGluR along visceral afferent pathways, the answers to which may reveal many more therapeutic candidates.
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