Metabotropic Glutamate Receptors and Neurological/Psychiatric Disorders

Editorial

22 March 2019

Editorial: Metabotropic Glutamate Receptors and Neurological/Psychiatric Disorders

Enza Palazzo

Volker Neugebauer

and

Sabatino Maione

2,097 views

4 citations

Editors

Enza Palazzo

Department of Experimental Medicine, University of Campania Luigi Vanvitelli

Sabatino Maione

University of Campania Luigi Vanvitelli

Volker Neugebauer

Texas Tech University Health Sciences Center

Impact

Review

08 February 2019

Role of Metabotropic Glutamate Receptors in Neurological Disorders

Rosalia Crupi

, 1 more and

Salvatore Cuzzocrea

Glutamate is a fundamental excitatory neurotransmitter in the mammalian central nervous system (CNS), playing key roles in memory, neuronal development, and synaptic plasticity. Moreover, excessive glutamate release has been implicated in neuronal cell death. There are both ionotropic and metabotropic glutamate receptors (mGluRs), the latter of which can be divided into eight subtypes and three subgroups based on homology sequence and their effects on cell signaling. Indeed, mGluRs exert fine control over glutamate activity by stimulating several cell-signaling pathways via the activation of G protein-coupled (GPC) or G protein-independent cell signaling. The involvement of specific mGluRs in different forms of synaptic plasticity suggests that modulation of mGluRs may aid in the treatment of cognitive impairments related to several neurodevelopmental/psychiatric disorders and neurodegenerative diseases, which are associated with a high economic and social burden. Preclinical and clinical data have shown that, in the CNS, mGluRs are able to modulate presynaptic neurotransmission by fine-tuning neuronal firing and neurotransmitter release in a dynamic, activity-dependent manner. Current studies on drugs that target mGluRs have identified promising, innovative pharmacological tools for the treatment of neurodegenerative and neuropsychiatric conditions, including chronic pain.

43,041 views

212 citations

Pharmacological blockade of mGlu5 receptors is anxiolytic without affecting sociability. Time spent (s) in the different compartments of the three-chambered apparatus by MTEP- and vehicle-treated (4% DMSO in saline) mice during the test, at 5 min (MTEP n = 13; vehicle n = 13) (A) or 1 h post-injection (MTEP n = 12; vehicle n = 12) (G). Time spent (s) in close proximity with the conspecific and object at 5 min (B) or 1 h post-injection (H). Preference index derived from the numerical difference between time spent in conspecific and object chamber divided by total time spent × 100 at 5 min (C) or 1 h post-injection (I). Index derived from the numerical difference between time spent in close proximity to conspecific and object divided by total time spent in close proximity × 100 at 5 min (D) or 1 h post-injection (J). Both social preference indexes did not differ between MTEP and vehicle-treated mice at any post-injection time. At 5 min (E) post-injection, but not at 1 h (K), MTEP-treated mice traveled a longer distance than vehicle-treated mice. In the light-dark test, both at 5 min (MTEP n = 13; vehicle n = 13) (F) and 1 h (MTEP n = 14; vehicle n = 14) (L) post-injection, mice treated with MTEP displayed anxiolytic-like activity, spending more time (%) in the lit area of the box than vehicle-treated mice. Boxplots represent median, upper and lower quartiles with 10th and 90th percentile whiskers. Mean is represented with a cross. ∗p < 0.05, ∗∗p < 0.01.

Original Research

19 February 2019

An Appraisal of the Influence of the Metabotropic Glutamate 5 (mGlu5) Receptor on Sociability and Anxiety

Arnau Ramos-Prats

, 4 more and

Francesco Ferraguti

4,496 views

21 citations

Review

04 January 2019

Emerging Trends in Pain Modulation by Metabotropic Glutamate Receptors

Vanessa Pereira

and

Cyril Goudet

Distribution of mGluRs throughout important areas involved in pain. For (A-F, J-L) pictures, masks with pseudo colors were used to color scale the relative expression level of mGluR transcripts across sections (scale displayed at the bottom of the figure). For (G-I, M-P), no expression filter was applied to recolour the ISH pictures. Image credit: Allen Institute. Masked ISH images of mGlu1 (A) and mGlu5 (B) transcripts in mice coronal section, notably in Thalamus and Amygdala. CeA (central nucleus of the amygdala) is magnified in the right panels (white dotted line, drawn according to the Allen Brain Atlas). Distribution of mGlu1 (B,C) and mGlu5 (E,F) mRNA in mice midbrain and medulla sections involved in descending modulation of pain. Magnification of the periaqueductal gray (PAG) and rostro ventral medulla (RVM) areas are shown in the right panels (white dotted line, drawn according to the Allen Brain Atlas). ISH images of mGlu3 (G) transcript in mice coronal section, notably in Thalamus and Amygdala. CeA is magnified in the left panel (white dotted line). Distribution of mGlu3 (H,I) mRNA in mice midbrain and medulla. Magnification of the PAG and RVM nucleus are shown in the left panels (white dotted line). Masked ISH images of mGlu4 (J) transcript in mice coronal section, notably in Thalamus and Amygdala. CeA is magnified in the left panel (white dotted line). Distribution of mGlu4 (K,L) mRNA in mice midbrain and medulla. Magnification of the PAG and RVM nucleus are shown in the left panels (white dotted line). Images are available for mGlu1 receptor (GMR1 gene) at http://mouse.brain-map.org/experiment/show/79591723, for mGlu5 receptor (GRM5 gene) at http://mouse.brain-map.org/experiment/show/73512423, for mGlu3 receptor (GMR3 gene) at http://mouse.brain-map.org/experiment/show/539, and for mGlu4 receptor (GRM4 gene) at http://mouse.brain-map.org/experiment/show/71247631. Distribution of mGlu1 (M), mGlu5 (N), mGlu3 (O), mGlu4 (P) transcripts in mice spinal cord. Bottom panels are magnification of the dorsal horn. Images are available for mGlu1 at http://mousespinal.brain-map.org/imageseries/show.html?id=100036413, for mGlu5 receptor at http://mousespinal.brain-map.org/imageseries/show.html?id=100033614, for mGlu3 receptor at http://mousespinal.brain-map.org/imageseries/show.html?id=100039062 and for mGlu4 receptor at http://mousespinal.brain-map.org/imageseries/show.html?id=100018200.

Pain is an essential protective mechanism meant to prevent tissue damages in organisms. On the other hand, chronic or persistent pain caused, for example, by inflammation or nerve injury is long lasting and responsible for long-term disability in patients. Therefore, chronic pain and its management represents a major public health problem. Hence, it is critical to better understand chronic pain molecular mechanisms to develop innovative and efficient drugs. Over the past decades, accumulating evidence has demonstrated a pivotal role of glutamate in pain sensation and transmission, supporting glutamate receptors as promising potential targets for pain relieving drug development. Glutamate is the most abundant excitatory neurotransmitter in the brain. Once released into the synapse, glutamate acts through ionotropic glutamate receptors (iGluRs), which are ligand-gated ion channels triggering fast excitatory neurotransmission, and metabotropic glutamate receptors (mGluRs), which are G protein-coupled receptors modulating synaptic transmission. Eight mGluRs subtypes have been identified and are divided into three classes based on their sequence similarities and their pharmacological and biochemical properties. Of note, all mGluR subtypes (except mGlu6 receptor) are expressed within the nociceptive pathways where they modulate pain transmission. This review will address the role of mGluRs in acute and persistent pain processing and emerging pharmacotherapies for pain management.

18,448 views

110 citations