ReviewGlutamate receptors and pain
Introduction
An accumulating body of evidence is emerging that supports the notion that modulation of glutamate receptors may have potential for therapeutic utility in several categories of persistent pain, including neuropathic pain resulting from injury and/or disease of central (e.g., spinal cord injury) or peripheral nerves (e.g., diabetic neuropathy, radiculopathy) and inflammatory or joint-related pain (e.g., rheumatoid arthritis, osteoarthritis). Symptoms associated with these classes of persistent pain can include hyperalgesia, an increased pain sensation to mildly noxious stimuli; allodynia, a pain associated with normally non-noxious stimuli; and spontaneous pain. While these forms of clinical persistent pain are distinct, they are all postulated to depend, at least in part, on long-term increases in synaptic efficacy of glutamatergic signaling in nociceptive pathways, often called central sensitization. Originally described as an enhanced level of synaptic transmission in dorsal horn neurons of the spinal cord following intense peripheral noxious stimuli, tissue injury or nerve damage [1], central sensitization is now apparent within glutamatergic pathways in supraspinal nociceptive regions [2]. Central sensitization leads to increases in responsiveness of dorsal horn neurons coupled with reductions in pain threshold (allodynia), amplification of pain responses (hyperalgesia) and spread of pain sensitivity to non-injured areas [3]. The long-term synaptic plasticity associated with central sensitization is proposed to be primarily expressed as phosphorylation-induced alterations in the biophysical properties of ionotropic glutamate receptors (i.e., NMDA and AMPA receptors) and/or promotion of AMPA receptor trafficking to the postsynaptic membrane. However, metabotropic glutamate receptors acting pre- or postsynaptically also have been shown to modulate the induction and/or maintenance of central sensitization [3]. In addition to alterations in pain pathways that underlie the salience of nociceptive transmission, an interplay between reward and aversion circuits in the CNS are thought to modulate the emotional aspects of persistent pain states [4]. This report will focus on the role of glutamate receptors, including ionotropic (AMPA, NMDA and kainate) and metabotropic (mGlu1-8) receptors, in persistent pain states with particular emphasis on their expression patterns in nociceptive pathways and their potential as targets for pharmacological intervention strategies.
Section snippets
AMPA receptor structure
The α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptors (AMPA) receptor family is comprised of four genes GLUA1–4 (GluR1–4 or GluRA-D) that encode distinct proteins having three transmembrane domains and a reentrant loop (P) believed to line the pore of the ion channel. Extracellular regions immediately adjacent to TM1 (designated S1), and between TM3 and TM4 (designated S2) have been crystallized and shown to form the ligand-binding core (LBC) having an upper and lower domain that
NMDA receptor structure
The NMDA receptor ion channel is a tetrameric structure that results from up to seven genes coding for seven subunits termed GLUN1, GLUN2A, GLUN2B, GLUN2C, GLUN2D, GLUN3A and GLUN3B [48], [49]. Multiple splice variants of the GLUN1 receptor subunit exist and the expression patterns of GLUN2 and GLUN3 subunits vary in development. Similar to AMPA receptors, each subunit is composed of three transmembrane spanning regions (TM1, TM3, TM4), an intramembrane loop (P) between the TM1 and TM2 thought
Kainate receptor structure
The kainate receptor family is comprised of five genes, divided into two subfamilies, including GLUK1 and GLUK2 (also known as KA1 and KA2) which exhibit higher affinity for kainate than members of the GLUK5–7 (also known as GluR5–7) subfamily [77]. Kainate receptors are formed by tetrameric assemblies of these subunits, and are likely to exist in either homomeric or heteromeric configurations. Although it appears that any combination of subunits can combine to form a kainate receptor,
mGlu receptor structure
The mGlu receptors are the products of eight genes (mGlu1-8) belonging to the larger family 3 (or C) class of G protein-coupled receptors (for review see [113]). mGlu receptors have been segregated into three groups on the basis of their amino acid sequence homology. Group I mGlu receptors include mGlu1 and mGlu5 receptor subtypes and their associated alternatively spliced variants, including mGlu1a,b,c,d and mGlu5a,b. The group II subclass consists of mGlu2 and mGlu3 receptors and the group
Concluding remarks
The role of ionotropic and metabotropic glutamate receptors in physiological and pathophysiological pain states has been advanced enormously in the past 15 years. This is in part due to the elucidation of specific subtypes/subunits for each receptor class, and the subsequent cloning and expression of recombinant receptors. In addition, the identification of molecules that are subtype-selective and systemically active has permitted investigation into the potential therapeutic utility of
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