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Diabetic sensory neuropathy (DSN) is a chronic condition that manifests itself as neuropathic pain and sensory alterations, for which there are no effective treatments available. Based on the well-described antinociceptive properties of bone marrow-derived mesenchymal stromal cells (BMMSC), we hypothesized that extracellular vesicles (EV) derived from BMMSC also have a therapeutic effect on painful neuropathies. To investigate the antinociceptive properties of EV-BMMSC in model of DSN. EV were obtained from the BMMSC supernatant and characterized by size, shape and density by transmission electron microscopy and Nanoparticle Tracking Analysis. NSD was induced in C57Bl6 mice by streptozotocin, and the nociceptive threshold was assessed by von Frey filaments. Thirty days after the model induction, mice were intravenously treated with 100 µL of saline, BMMSC (1 × 106) or EV-BMMSC. The involvement of the opioid system was investigated by using the antagonist reversal assay. The expression of preproencephalin gene was analyzed by RT-qPCR. Approximately one million BMMSC were able to produce 4.4 × 108 VE, ranging from 52.4 to 450 nm, corresponding to microvesicles and exosomes. Transmission electron microscopy confirmed its VE-like morphology. A single intravenous administration of BMMSC or EV-BMMSC was able to reverse the behavioral signs of neuropathic pain (p <0.05). Systemic administration of naloxone (3 mg / kg, via i.p), a non-selective opioid receptor antagonist, reversed the antinociception induced by BMMSC and VE-BMMSC (p <0.05). RT-qPCR analyzes 7 days after treatments indicated increased levels of preproencephalin mRNA in the spinal cord of neuropathic mice treated with BMMSC and VE- BMMSC, when compared to the saline treated mice (p <0.001). Sixty days after treatments, neuropathic mice treated with EV-BMMSC still exhibited increased expression of preproencephalin in the spinal cord (p <0.01). Analysis of the BMMSC secretetoma showed that these cells are able of secreting preproencephalin into the extracellular medium. EV-BMMSC preserve the antinociceptive properties of the source cells, producing antinociceptive effects associated with the activation of endogenous opioid systems. [ABSTRACT FROM AUTHOR]