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

Abstract

The dorsal striatum, apart from controlling voluntary movement, displays a recently demonstrated pain inhibition. It is connected to the descending pain modulatory system and in particular to the rostral ventromedial medulla through the medullary dorsal reticular nucleus. Diseases of the basal ganglia, such as Parkinson's disease, in addition to being characterized by motor disorders, are associated with pain and hyperactivation of the excitatory transmission. A way to counteract glutamatergic hyperactivation is through the activation of group III metabotropic glutamate receptors (mGluRs), which are located on presynaptic terminals inhibiting neurotransmitter release. So far the mGluRs of group III have been the least investigated, owing to a lack of selective tools. More recently, selective ligands for each mGluR of group III, in particular positive and negative allosteric modulators, have been developed and the role of each subtype is starting to emerge. The neuroprotective potential of group III mGluRs in pathological conditions, such as those characterized by elevate glutamate, has been recently shown. In the dorsal striatum, mGluR7 and mGluR8 are located at glutamatergic corticostriatal terminals and their stimulation inhibits pain in pathological conditions such as neuropathic pain. The two receptors in the dorsal striatum have instead a different role in pain control in normal conditions. This review will discuss recent results focusing on the contribution of mGluR7 and mGluR8 in the dorsal striatal control of pain. The role of mGluR4, whose antiparkinsonian activity is widely reported, will also be addressed.

Novel Molecular Hallmarks of Group 3 Medulloblastoma by Single-Cell Transcriptomics

“…GRM8 encodes MGLUR8, a G-protein coupled glutamate receptor reported to significantly influence the risk of diseases affecting the CNS including behavior, mental disorder, cognition as well as tumorigenesis of the CNS and other systems ( 28 – 30 ). Of note, GRM8 expression has been shown to characterize Group 4 MB ( 47 ) which overlaps in molecular features with Group 3 tumors.…”

“…The marker genes of this specific cluster were selected, followed by validation and selection, performed with tumor samples from 33 patients with Group 3 MB. Consequently, we unearthed the GRM8 gene, encoding metabotropic glutamate receptor 8 (MGLUR8), a G-protein coupled glutamate receptor reported to significantly influence the risk of central nervous system (CNS) disease (28)(29)(30), and the AP1S2 gene, encoding AP-1 complex subunit sigma-2, a component of adaptor protein complex 1 and correlating with CNS disorder (31), as novel hallmarks linked to poor prognosis of Group 3 MB. Thus, our findings identified GRM8 and AP1S2 as potential targets for treatment of patients with MYC+ Group 3 MB in the future.…”

International Union of Basic and Clinical Pharmacology. CXI. Pharmacology, Signaling, and Physiology of Metabotropic Glutamate Receptors

“…Furthermore, the potentiation of mGlu 7 receptor activity improves cognitive and social deficits, as well as respiratory impairments, in a mouse model of Rett syndrome (Gogliotti et al, 2017). Interestingly, depending on the brain structure, mGlu 7 and mGlu 8 receptors play opposing roles in pain (Boccella et al, 2020). For example, mGlu 7 receptor activation in periaqueductal gray and amygdala is pronociceptive, whereas mGlu 8 receptor activation is antinociceptive (Marabese et al, 2007;Palazzo et al, 2008).…”

Efficacy of Essential Oils in Pain: A Systematic Review and Meta-Analysis of Preclinical Evidence

“…The EO of bergamot can modulate the synaptic level of glutamate and this occurs when it is used as a bergapten-free fraction ( Morrone et al, 2007 ). Hence, a mixture of monoterpene hydrocarbons within the volatile fraction may be responsible for bergamot analgesic activity since glutamate is significantly involved in the pain descending pathway due to metabotropic glutamate receptors mGluR7 and mGluR8 ( Boccella et al, 2020 ). The novel phytocannabinoid cannabidihexol, with the terpenophenolic core of cannabidiol and Δ9-tetrahydrocannabinol, has proven to significantly reduce the late phase of the formalin test at low doses in C57BL/6J mice ( Linciano et al, 2020 ).…”