The GluRA, B, C of pain

It is becoming increasingly clear that synaptic plasticity in pain-sensitive pathways has many features in common with better understood forms of synaptic plasticity, such as hippocampal long-term potentiation. Now Hartmann and colleagues have shown that AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors, which are vital mediators of hippocampal plasticity, are also important modulators of inflammatory pain and of synaptic plasticity in the spinal nociceptive system.

Most AMPA receptors in the central nervous system — those that contain the GluRB subunit together with GluRA, C or D subunits — have low permeability to Ca²⁺. However, receptors that lack the GluRB subunit have much higher Ca²⁺ permeability, and many of these receptors are found in the spinal dorsal horn. AMPA receptors in the dorsal horn are also unusual in that they are found presynaptically on the axon terminals of primary sensory afferent neurons, and activation of these receptors depolarizes the afferent neurons and thereby reduces neurotransmission from afferent fibres to second-order neurons in the spine.

Hartmann et al. set out to investigate the possible importance of Ca²⁺-permeable AMPA receptors in the dorsal horn in nociceptive plasticity and inflammatory pain, using mutant mice that lack the GluRA, B or C subunits. Basal levels of neurotransmission and acute responses to painful stimuli were normal in these mice, but the Ca²⁺ permeability and ion conductance properties of the AMPA receptors in the dorsal horn were not: in GluRA^−/− mice there were fewer Ca²⁺-permeable AMPA receptors and the AMPA channel currents were reduced, whereas the opposite was true in GluRB^−/− mice.

To study the effects of these subunits on spinal plasticity, the authors used phosphorylation of ERK1/2 (extracellular receptor-activated MAP kinase 1 and 2) as a marker for synaptic plasticity. In wild-type and GluRB^−/− mice, high-frequency activation of C-fibre inputs in the dorsal root led to increased phosphorylation of ERK1/2, but this did not occur in GluRA^−/− mice (which have fewer ^Ca2+-permeable AMPA receptors). So GluRA-containing AMPA receptors are essential for synaptic plasticity reflected by ERK1/2 phosphorylation in the spinal cord.

What is the significance of these findings for pain perception in vivo? Although the mutant mice showed normal responses to acute painful stimuli, GluRB^−/− mice showed significantly more hyperalgesia than either wild-type or GluRA^−/− mice in a model of chronic inflammatory pain that involved injecting the hindpaw with an irritant. Moreover, in a test of rapid sensitization of pain pathways, GluRA^−/− mice showed less sensitization and GluRB^−/− mice showed more.

The results of this study show that the GluRA and GluRB subunits of AMPA receptors, which control the Ca²⁺ permeability of the receptors and can also influence their trafficking and synaptic availability, have opposing effects on synaptic plasticity in spinal pathways in vitro and on inflammatory pain in vivo. These findings add to our understanding of pain perception, and might help to drive the development of treatments for chronic pain conditions.