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

Abstract 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.