Potentiation of visualized exosomal miR-1306-3p from primary sensory neurons contributes to chronic visceral pain via spinal P2X3 receptors

Exosomes served as "communicators" to exchange information among different cells in the nervous system. Our previous study demonstrated that the enhanced spinal synaptic transmission contributed to chronic visceral pain in irritable bowel syndrome. However, the underlying mechanism of primary sensory neuron (PSN)-derived exosomes on spinal transmission remains unclear. In this study, an exosome visualization method was established to specifically track exosomes derived from PSNs in CD63-GFP f/+ (green fluorescent protein) mice. Neonatal maternal deprivation (NMD) was adopted to induce chronic visceral pain in CD63-GFP f/+ male mice. The exosome visualization technology demonstrated that NMD increased visible PSN-derived exosomes in the spinal dorsal horn, enhanced spinal synaptic transmission, and led to visceral pain in CD63-GFP f/+ male mice. The PSN-derived exosomal miR-1306-3p sorted from spinal dorsal horn activated P2X3R, enhanced spinal synaptic transmission, and led to visceral pain in NMD mice. Moreover, upregulation of Rab27a in dorsal root ganglia mediated the increased release of PSN-derived exosomes, and intrathecal injection of siR-Rab27a reduced visible PSN-derived exosomes in spinal cord, suppressed spinal synaptic transmission, and alleviated visceral pain in NMD mice. This and future studies would reveal the detailed mechanisms of PSN-derived exosomes and provide a potential target for clinical treatment of chronic visceral pain in patients with irritable bowel syndrome.