Translocation of GluR1-Containing AMPA Receptors to a Spinal Nociceptive Synapse during Acute Noxious Stimulation

Abstract

/calmodulindependent protein kinase II (CaMKII)-dependent pathway, has been proposed to underlie certain forms of hyperalgesia, the enhanced pain sensitivity that may accompany inflammation or tissue injury. However, the specific synaptic populations that may be subject to such plasticity have not been identified. Using neuronal tracing and postembedding immunogold labeling, we show that a model of acute inflammatory hyperalgesia is associated with an elevated density of GluR1-containing AMPA receptors, as well as an increased synaptic ratio of GluR1 to GluR2/3 subunits, at synapses established by C-fibers that lack the neuropeptide substance P. A more subtle increase in GluR1 immunolabeling was noted at synapses formed by substance P-containing nociceptors. No changes in either GluR1 or GluR2/3 contents were observed at synapses formed by low-threshold mechanosensitive primary afferent fibers. These results contrast with our previous observations in the same pain model of increased and decreased levels of activated CaMKII at synapses formed by peptidergic and nonpeptidergic nociceptive fibers, respectively, suggesting that the observed redistribution of AMPA receptor subunits does not depend on postsynaptic CaMKII activity. The present ultrastructural evidence of topographically specific, activity-dependent insertion of GluR1-containing AMPA receptors at a central synapse suggests that potentiation of nonpeptidergic C-fiber synapses by this mechanism contributes to inflammatory pain.

SNO-ing at the Nociceptive Synapse?

“…Blocking or deletion of AMPA receptor subunits therefore reduces glutamate-dependent signaling and alleviates hyperalgesia and allodynia in rodent models of inflammatory or neuropathic pain (Garry et al, 2003;Larsson and Broman, 2008;Luo et al, 2008). Synaptic plasticity at glutamatergic synapses is mediated by changes in the surface expression of AMPA receptors (Fig.…”

“…NMDA receptor-mediated activation of nNOS resulted in increased S-nitrosylation of stargazin (Figs. 3, 5, and 6) and, subsequently, increased binding and surface expression of the AMPA receptor subunit GluR1 (Selvakumar et al, 2009) suggesting a nitric-oxide-dependent feed-forward activation that may contribute to the development of hyperalgesia. Inflammatory hyperalgesia is associated with an increase of the membrane density of GluR1-containing AMPA receptors in nociceptive neurons of the dorsal horn of the spinal cord and a relative decrease of GluR2/3 subunits (Larsson and Broman, 2008). Deletion models revealed that a lack of GluR2 intensifies long-term potentiation upon tetanic stimulation (Jia et al, 1996;Youn et al, 2008).…”

Nerve Injury Increases GluA2-Lacking AMPA Receptor Prevalence in Spinal Cords: Functional Significance and Signaling Mechanisms

“…Acute inflammatory pain is associated with increased insertion of GluA1-containing AMPARs in the spinal dorsal horn (Galan et al, 2004;Larsson and Broman, 2008), and GluA2 internalization mediated by protein kinase C (PKC) activation is associated with persistent inflammatory pain (Park et al, 2009). In addition, stimulation of N-methyl-D-aspartate receptors (NMDARs) can induce GluA2 internalization in the hippocampus and hypothalamus (Tigaret et al, 2006;Li et al, 2012).…”

Contextual learning requires synaptic AMPA receptor delivery in the hippocampus

“…AMPARs are ionotropic glutamate receptors and form heterotetramers, comprised of a combination of four subunits (GluR1-GluR4) (9,10). A number of studies demonstrated that synaptic insertion of GluR1-containing AMPARs contributes to the synaptic potentiation during LTP and experience-dependent neuronal plasticity (8,(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24).…”