Injured SSTR2⁺ nociceptor axons in neuromas drive chronic spontaneous neuropathic pain

Spontaneous pain is a very common but poorly understood consequence of peripheral nerve injury. We developed a system for measuring spontaneous pain-related behaviors in mice over months, which revealed that limb flicks—emerging predominantly 2 months post-injury—reflect spontaneous pain, and that neuromas are the drivers of this component of neuropathic pain. In vivo dorsal root ganglion imaging showed that small-diameter sensory neurons are the source of spontaneous ectopic neuroma activity and are different from the intact neurons that drive stimulus-evoked pain. Cell–specific optogenetic stimulation studies identified that injured SSTR2 + sensory axons in neuromas are the triggers of spontaneous limb flicks/neuropathic pain. These findings reveal the mechanisms of spontaneous neuropathic pain and open new therapeutic opportunities.