Mesenchymal Stromal Cells Play an Analgesic Role through a Npy2r Sensory Neuron-Mediated Lung-to-Brain Axis

Mesenchymal stromal cells (MSC) have emerged as a promising therapeutic option for neuropathic pain (NP), but the mechanisms remain elusive. Using murine pain models, we demonstrated that MSC effectively alleviate pain, with efficacy comparable to dexmedetomidine, a moderate analgesic. Mechanistically, peripheral delivery of MSC activated pulmonary Npy2r-expressing vagal sensory neurons, which project to the nucleus tractus solitarius and ventral lateral periaqueductal gray area, driving analgesia via the vagal lung-to-brain pathway. Chemogenetic activation of Npy2r sensory neurons similarly ameliorated spared nerve injury (SNI)-induced mechanical allodynia and thermal hyperalgesia. Furthermore, we found that MSC-derived extracellular ATP, released via pannexin1, activated Npy2r sensory neurons through purinergic receptor P2X2 (P2rx2). Strikingly, inhalation of a P2rx2 agonist produced significant therapeutic effects in SNI mice. Together, our findings reveal that Npy2r sensory neuron-mediated lung-brain axis underlies MSC-induced analgesia and highlight the potential of targeting body-brain pathways for novel NP treatments.