Glutamate receptors and pain

doi:10.1016/j.semcdb.2006.10.008

Seminars in Cell & Developmental Biology

Volume 17, Issue 5, October 2006, Pages 592-604

https://doi.org/10.1016/j.semcdb.2006.10.008 Get rights and content

Abstract

Pain is an important survival and protection mechanism for animals. However, chronic/persistent pain may be differentiated from normal physiological pain in that it confers no obvious advantage. An accumulating body of pharmacological, electrophysiological, and behavioral evidence is emerging in support of the notion that glutamate receptors play a crucial role in pain pathways and 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). This review focuses on the role of glutamate receptors, including both 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.

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 GLU_A1–4 (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 GLU_N1, GLU_N2A, GLU_N2B, GLU_N2C, GLU_N2D, GLU_N3A and GLU_N3B [48], [49]. Multiple splice variants of the GLU_N1 receptor subunit exist and the expression patterns of GLU_N2 and GLU_N3 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 GLU_K1 and GLU_K2 (also known as KA1 and KA2) which exhibit higher affinity for kainate than members of the GLU_K5–7 (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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ReviewGlutamate receptors and pain

Abstract

Introduction

Section snippets

AMPA receptor structure

NMDA receptor structure

Kainate receptor structure

mGlu receptor structure

Concluding remarks

Trends Neurosci

Neuron

Neurosci Lett

Brain Res

Neurosci Lett

Brain Res

Brain Res

Brain Res Mol Brain Res

Neuron

Neuroscience

Brain Res Mol Brain Res

Neuron

Neuroscience

Pain

Pain

Brain Res Mol Brain Res

Brain Res

Pain

Neurosci Lett

Pain

Brain Res

Pain

Mol Cell Neurosci

Neuropharmacology

Neuropharmacology

Neuroscience

Pain

Brain Res

Neuropharmacology

Pain

Pain

Trends Neurosci

Neuroscience

Pain

Brain Res

Brain Res

Pain

Neurosci Lett

Cell

Neuropharmacology

Prog Neurobiol

Neuron

Neuron

Pain

Neuron

Evidence for a central component of post-injury pain hypersensitivity

Nature

Dynamic neuronal responses in cortical and thalamic areas during different phases of formalin test in rats

Exp Neurol

Reward-aversion circuitry in analgesia and pain: Implications for psychiatric disorders

Eur J Pain

Identification of a site in glutamate receptor subunits that controls calcium permeability

Science

Differential dependence on GluR2 expression of three characteristic features of AMPA receptors

J Neurosci

Review
Glutamate receptors and pain