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Supraspinal metabotropic glutamate receptors: a target for pain relief and beyond
Author(s) -
Palazzo Enza,
Marabese Ida,
Novellis Vito,
Rossi Francesco,
Maione Sabatino
Publication year - 2014
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/ejn.12398
Subject(s) - metabotropic glutamate receptor , glutamate receptor , neuroscience , glutamatergic , metabotropic glutamate receptor 1 , ionotropic effect , metabotropic glutamate receptor 8 , metabotropic receptor , metabotropic glutamate receptor 2 , metabotropic glutamate receptor 5 , metabotropic glutamate receptor 6 , metabotropic glutamate receptor 7 , neurotransmission , receptor , chemistry , pharmacology , biology , medicine
Glutamate is the main excitatory neurotransmitter in the central nervous system, controlling the majority of synapses. Apart from neurodegenerative diseases, growing evidence suggests that glutamate is involved in psychiatric and neurological disorders, including pain. Glutamate signaling is mediated via ionotropic glutamate receptors (i G lu R s) and metabotropic glutamate receptors (m G lu R s). So far, drugs acting via modulation of glutamatergic system are few in number, and all are associated with i G lu R s and important side effects. The glutamatergic system may be finely modulated by m G lu R s. Signaling via these receptors is slower and longer‐lasting, and permits fine‐tuning of glutamate transmission. There have been eight m G lu R s cloned to date (m G lu R 1–m G lu R 8), and these are further divided into three groups on the basis of sequence homology, pharmacological profile, and second messenger signaling. The pattern of expression of m G lu R s along the pain neuraxis makes them suitable substrates for the design of novel analgesics. This review will focus on the supraspinal m G lu R s, whose pharmacological manipulation generates a variety of effects, which depend on the synaptic location, the cell type on which they are located, and the expression in particular pain modulation areas, such as the periaqueductal gray, which plays a major role in the descending modulation of pain, and the central nucleus of the amygdala, which is an important center for the processing of emotional information associated with pain. A particular emphasis will also be given to the novel selective m G lu R subtype ligands, as well as positive and negative allosteric modulators, which have permitted discrimination of the individual roles of the different m G lu R subtypes, and subtle modulation of central nervous system functioning and related disorders.