Neuropathic pain caused by mis-wiring and abnormal end organ targeting

Nerve injury leads to chronic pain and exaggerated sensitivity to gentle touch (allodynia) as well as loss of sensation in the areas where injured and non-injured nerves comingle1-3. Mechanisms disambiguating these mixed and paradoxical symptoms are unknown. Here, we longitudinally and non-invasively imaged genetically-labelled populations of fibres sensing noxious stimuli (nociceptors) and gentle touch (low threshold afferents) peripherally in the skin for longer than 10 months post-nerve injury while simultaneously tracking pain-related behaviour in the same mice. Fully denervated skin areas initially lost sensation, gradually recovered normal sensitivity and unexpectedly developed marked allodynia and aversion to gentle touch several months post-injury. This reinnervation-associated neuropathic pain involved nociceptors that sprouted into denervated territories precisely reproducing the initial pattern of innervation, were guided by blood vessels and showed irregular terminal connectivity in the skin and lowered activation thresholds mimicking low-threshold afferents. In contrast, low threshold afferents, which normally mediate touch sensation as well as allodynia in intact nerve territories post- injury4-7, failed to reinnervate, leading to an aberrant state of apposition of tactile end organs, such as Meissner corpuscles, with nociceptors alone. Genetic ablation of nociceptors fully abrogated reinnervation allodynia. Our results thus demonstrate the emergence of a novel form of chronic neuropathic pain driven by structural plasticity, abnormal terminal connectivity and malfunction of nociceptors during reinnervation, providing a mechanistic framework for the paradoxical sensory manifestations observed clinically and imposing a heavy burden on patients.