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, it is demonstrated that MSC effectively alleviates 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, drives analgesia via the vagal lung-to-brain pathway. Chemogenetic activation of Npy2r sensory neurons similarly ameliorates spared nerve injury (SNI)-induced mechanical allodynia and thermal hyperalgesia. Furthermore, it is found that MSC-derived extracellular ATP, released via pannexin1, activates Npy2r sensory neurons through purinergic receptor P2X2 (P2rx2). Strikingly, inhalation of a P2rx2 agonist produced significant therapeutic effects in SNI mice. Together, these 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.