Derivation of AMPA receptor GluA1 subunits in mice from exosomes modulates inflammatory pain

Abstract

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid–type (AMPA-type) glutamate receptors (AMPARs) play a crucial role in synaptic plasticity within the central nervous system. While there is anatomical evidence suggesting the presence of AMPAR expression in the peripheral nervous system, the functional significance of these receptors in vivo remains unclear.   The nociceptor-specific deletion of GluA1 results in the disruption of calcium permeability and a diminished response to capsaicin stimulation in nociceptors. The deletion of GluA1, leds to reduced mechanical hypersensitivity and sensitization in models of chronic inflammatory pain and arthritis. There is known that GluA1-containing AMPARs played a regulatory role in the nociceptors' responses to painful stimuli in inflamed tissues, influencing the excitatory signals transmitted from the periphery into the spinal cord.  Exosomes, nanoscale particles secreted by cells (typically ranging from 30 to 150 nm in size), carry a diverse array of biological molecules, including nucleic acids, proteins, and lipids. Exosomes have crucial role in facilitating intercellular communication. Leveraging their inherent stability, low immunogenicity, and impressive tissue/cell penetration capabilities, exosomes show promise as advanced platforms for targeted drug and gene delivery.  To address this issue, we used mice specifically lacking of the key AMPAR subunits, GluA1, in peripheral, pain-sensing neurons (nociceptors), while preserving expression of these subunits in the central nervous system. Nociceptor-specific deletion of GluA1 led to disruption of calcium permeability and reduced capsaicin-evoked activation of nociceptors. Deletion of GluA1, led to reduced mechanical hypersensitivity and sensitization in models of chronic inflammatory pain and arthritis. We generated exosomes containing GluA1 and introduced them to mice around nociceptors, observing a reverse effect compared to GluA1 deletion. Mice treated with exosomes were more sensitive to pain.