Nociception modulation by supraspinal group III metabotropic glutamate receptors

Abstract

The modulatory actions of glutamate, the main excitatory neurotransmitter in the central nervous system (CNS), are exerted through the activation of metabotropic glutamate receptors (mGluRs). Of the eight known mGluRs (mGluR1-8), group III mGluRs (mGluR4, mGluR6, mGluR7, and mGluR8) are less understood because of the lack of selective ligands. Except for mGluR6, group III mGluRs are widely distributed throughout the CNS. They are mainly located on presynaptic terminals where they inhibit neurotransmitter release at glutamatergic and caminobutyric acid (GABA)ergic synapses. Their location at certain synapses is considered critical for normal CNS function, which makes them potential targets in neurological and psychiatric treatments. Novel ligands that are selective for group III mGluR subtypes have recently been developed. These compounds, which mainly target allosteric sites and act as positive or negative allosteric modulators (PAMs or NAMs) of glutamate transmission, are contributing to the understanding of the functional roles of group III mGluRs in a number of pathological conditions, such as epilepsy, anxiety, neurodegenerative diseases, and chronic pain. Moreover, the presence of group III mGluRs throughout the entire pain neuraxis and particularly in the descending system suggests that these endogenous substrates that extend from the cortex to the first spinal synapse are candidates for pain control. Recent data on chronic pain alleviation by group III mGluR ligands encourage further studies as pathological pain is one of the most troublesome diseases because of the current lack of satisfactory therapy. This review summarizes recent studies on group III mGluRs in animal models of chronic pain, which evidence an opposite modulation of mGluR7 and mGluR8 on pain responses and their capability to affect pain responses only in pathological states.

Metabotropic Glutamate Receptors in Glial Cells: A New Potential Target for Neuroprotection?

“…Microglial activation significantly contributes to central sensitization and neurodegeneration promoting the transition from acute to chronic pain ( Ji et al, 2014 ; Hossain et al, 2017 ). According to this scenario mGlu receptors expressed on glial cells (microglia and astrocytes) might exert a key role in the pathogenesis of chronic pain by modulating both glutamate release and neuroinflammatory phenomena ( Chiechio, 2016 ; Palazzo et al, 2017 ).…”

A Review of Molecular Imaging of Glutamate Receptors

“…The mGluR7 receptor, which is also sensitive to L -AP4, showed moderate mRNA expression in neocortex, limbic cortex, hippocampus, and many other regions including septum, amygdala, specific hypothalamic nuclei and locus coeruleus [ 224 ]. The selective mGluR8 agonist ( S )-3,4-dicarboxyphenylglycine has analgesic properties, perhaps in-keeping with the distribution across the pain neuraxis [ 225 ]. There are no reports of ligands or allosteric modulators suitable for imaging of mGluR6, 7, or 8.…”

The Modulation of Pain by Metabotropic Glutamate Receptors 7 and 8 in the Dorsal Striatum

“…The perfusion with AMN082 into the CeA by reverse microdialysis decreased spinal withdrawal reflex threshold in healthy rats whereas it was devoid of activity in arthritic rats [170]. However, this lack of effect of AMN082 in pathological conditions is just the opposite to what has been found for mGluRs of group III, the modulation of which is effective only during chronic pain conditions [32,33,141,[170][171][172][173][174][175][176]. Differently, from the PAG and CeA, AMN082 locally administered into the nucleus tractus solitarius, NTS, inhibited cardiac nociception induced by pericardial capsaicin in rats [177].…”