Chemotherapy-induced neuropathic pain (CINP) is a severe side effect of commonly used chemotherapeutics, such as oxaliplatin, paclitaxel, and vincristine. It is characterized by mechanical or cold allodynia in a glove- and stocking-distribution, significantly lowering the life quality of cancer survivors and even resulting in chemotherapy discontinuation. However, the pathophysiological mechanism underlying CINP remains unclear, and its current first-line treatment, including antidepressants or anticonvulsants, often does not provide satisfactory pain relief, but is accompanied by diverse adverse outcomes, such as dizziness, nausea, vomiting, somnolence, or even organ damage. Therefore, it is necessary to identify the novel mechanisms and treatment targets for CINP.

Hypersensitivity or hyperexcitability of dorsal root ganglion (DRG) sensory neurons, as well as the upregulation of diverse pro-nociceptive mediators in neurons are involved in the onset and maintenance of chronic pain after chemotherapeutics treatment (Iseppon et al., 2023; Villalba-Riquelme et al., 2022). The DRG is absent of blood-brain barrier protection. Meanwhile, the endothelial cells that vascularize the DRG have large fenestrations and are permeable to various exogenous agents, including chemotherapeutics (Jimenez-Andrade et al., 2008). Platinum-based drugs can induce DNA damage and apoptosis in DRG neurons (Kanat et al., 2017). Paclitaxel can upregulate transient receptor potential vanilloid 1 (TRPV1) expression in DRG neurons and promote calcitonin gene-related peptide (CGRP) and substance P release (Wang et al., 2022). However, sensory neuron activity in the DRG also depends on neuron-glia crosstalk (Ren and Dubner, 2008). Sensory neurons in the DRG are surrounded by satellite glial cells (SGCs), which can produce glutamate and chemokines to sensitize laboring neurons (Ji et al., 2019). Noxious stimulation can induce neurons to release adenosine triphosphate, which activates P2X7 receptors in SGCs to release tumor necrosis factor (TNF) to further increase neuronal excitability (Zhang et al., 2007). Collectively, we proposed that exploring possible glia-neuron communication might provide new insights into the pathophysiological mechanism underlying DRG neuron sensitization.

As early as 2013, Warwick et al. observed that oxaliplatin or taxol could promote the activation of glial fibrillary acidic protein (GFAP) in SGCs and increase gap junction-mediated coupling among SGCs. Treatment with the gap junction blocker, carbenoxolone, produced an analgesic effect (Warwick and Hanani, 2013). However, carbenoxolone is not only a gap junction blocker. It can also inhibit P2X7 receptor-mediated exosome secretion in murine macrophages (Qu et al., 2007). Exosomes are membrane-enclosed extracellular vesicles that range in size from 30 to 100 nm. As intercellular communication carriers, exosomes can stably carry nucleic acids (DNA, noncoding RNAs, mRNAs), proteins, and lipids to regulate recipient cell or organ function (Jan et al., 2019). SGCs also secrete extracellular vesicles (Vinterhøj et al., 2019). Furthermore, they tightly wrap around the sensory neurons, with a distance between glial and neuronal surfaces of only approximately 20 nm, allowing an extensive exchange of chemicals between these two cell types (Hanani, 2005). Exosomes from microglia are involved in diverse neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (Guo et al., 2021). Considering all of these results, we aimed to determine whether the analgesic effect of carbenoxolone in Warwick et al.'s study was partially related to carbenoxolone's inhibition of exosome secretion in SGCs and the following interruption of exosomes mediating glia–neuron communication in the DRG.

Thus, in this study, we cultured SGCs and sensory neurons from the DRG of mice, treated SGCs with oxaliplatin, and examined the activation of SGCs. SGC-secreted exosomes after in-vitro oxaliplatin treatment were collected, identified, incubated with DRG neurons, and intrathecally injected into naïve mice. Thereafter, we detected the percentage of reactive oxygen species (ROS)-positive neurons, acid-sensing ion channel 3 (ASIC3) and TRPV1 expressions in neurons, and mechanical withdrawal threshold and TRPV1 expression in the DRG of mice. Furthermore, differentially expressed (DE) miRNAs within the SGC-secreted exosomes were detected, and their functions were predicted. Finally, the DE miRNAs with pain regulation potential were identified in silico.