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

Spontaneous pain is a common but poorly understood consequence of peripheral nerve injury1-3, including injuries that lead to the formation of neuromas4,5. We developed a chronic neuroma model for measuring spontaneous pain-related behaviours in mice, which revealed that limb flicks - emerging predominantly 2 months post-injury - reflect spontaneous paroxysmal pain. Ectopic activity of injured dorsal root ganglia (DRG) sensory neurons whose axonal endings terminate within the neuroma drives this spontaneous pain. In vivo imaging showed that a subset of small-diameter DRG sensory neurons are the source of spontaneous neural signals emanating from the neuroma, and these spontaneously active neurons are distinct from the intact larger diameter sensory neurons that mediate stimulus-evoked mechanical allodynia from spared nerves. Cell-type-specific gain- and loss-of-function studies identified a genetically- and functionally-defined subtype of small-diameter C-fibre nociceptors whose injured axons in neuromas drive spontaneous limb flicks/neuropathic pain. These findings establish the neurobiological basis of spontaneous pain enabling targeted pain management strategies and define a cellular and mechanistic separation between spontaneous and evoked neuropathic pain.