Spinal AMPA receptors: Amenable players in central sensitization for chronic pain therapy?

Abstract

The activity-dependent trafficking of AMPA receptors (AMPAR) mediates synaptic strength and plasticity, while the perturbed trafficking of the receptors of different subunit compositions has been linked to memory impairment and to causing neuropathology. In the spinal cord, nociceptive-induced changes in AMPAR trafficking determine the central sensitization of the dorsal horn (DH): changes in AMPAR subunit composition compromise the balance between synaptic excitation and inhibition, rendering interneurons hyperexcitable to afferent inputs, and promoting Ca²⁺ influx into the DH neurons, thereby amplifying neuronal hyperexcitability. The DH circuits become over-excitable and carry out aberrant sensory processing; this causes an increase in pain sensation in central sensory pathways, giving rise to chronic pain syndrome. Current knowledge of the contribution of spinal AMPAR to the cellular mechanisms relating to chronic pain provides opportunities for developing target-based therapies for chronic pain intervention.

Keywords: AMPA receptors; AMPAR trafficking; GluA1-4 subunits; chronic pain; nociceptive circuits; sensory DH neurons; the dorsal horn (DH) of the spinal cord.

Figure 1.

Spinal AMPAR trafficking for nociceptive signaling in normal (healthy) and chronic pain states. (a) After exocytosis from the intracellular stores such as the endoplasmic reticulum (ER), AMPAR laterally diffuse across the extrasynaptic plasma membrane to and from the postsynaptic density (PSD), undergoing constituent endocytosis/exocytosis cycles via recycling endosomes until are immobilized within the nanodomains of the receptors at PSD. (b) In chronic pain, the long-lasting activation of nociceptive afferents triggers the mobilization of the GluA2-containing AMPAR at PSD and the receptors undergo internalization from the synapses (blue arrow) followed by degradation (endocytosis via recycling endosomes). The GluA1-containing AMPAR replenish a pool of surface receptors and are mobilized to synapses (red arrow) to replace the GluA2-containing AMPAR within the nanodomains at PSD. Such a re-arrangement of the spinal AMPAR of different subunit compositions represents nociceptive plasticity in central pain pathways for the chronic pain maintenance

Figure 2.

Nociceptive-induced changes in the trafficking of spinal AMPAR (neuronal level) cause a broken balance between synaptic excitation and inhibition that leads to overall hyper-excitability and central sensitization of the DH (network level); aberrant signaling in central pain pathways turns pain chronic (systemic level). Various scenarios for targeting the broken GluA1 and/or GluA2 recycling can be implemented to suppress the AMPAR-mediated nociceptive plasticity, and recover the relative balance between neuronal excitation and inhibition in the DH circuits, thereby alleviating chronic pain