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Because of the incomplete understanding of the molecular mechanisms that underlie chronic pain, the currently available treatments for this type of pain remain inefficient. In this study, we show that Netrin-4, a member of the axon guidance molecule family, was expressed in dorsal horn inner lamina II excitatory interneurons in the rat spinal cord. A similar expression pattern for Netrin-4 was also observed in human spinal cord. Behavioral analysis revealed that tactile and heat hyperalgesia after peripheral nerve injury or inflammation were abolished in Netrin-4-mutant rats. Transient suppression of Netrin-4 or its receptor Unc5B after injury could also prevent allodynia. Conversely, intrathecal administration of Netrin-4 protein to naive rats enhanced excitatory synaptic transmission in the dorsal horn and induced allodynia, suggesting that Netrin-4 is involved in spinal sensitization. Furthermore, the Unc5B receptor and subsequent activation of the tyrosine phosphatase SHP2 mediated Netrin-4-induced pain signaling in the spinal cord. These results identify Netrin-4 as a novel protein regulating spinal sensitization leading to chronic pain. Our findings provide evidence for the function of Netrin in the adult nervous system, as well as a previously unknown function in inducing pain signals from dorsal horn interneurons.

Dorsal horn interneuron-derived Netrin-4 contributes to spinal sensitization in chronic pain via Unc5B