Contribution of proneurotrophin-3 to nerve trauma-induced neuropathic pain through promoting TrkC-mediated increase of CCL2 in primary sensory neurons.

Neuropathic pain induced by nerve trauma remains a substantial and unresolved clinical challenge. Despite ongoing research, therapeutic options for this disorder remain inadequate. Here, we report that neurotrophin-3 (Nt3) mRNA and its encoded proneurotrophin-3 (proNT3) protein are upregulated in neurons of the injured dorsal root ganglion (DRG), but not in the spinal cord, following peripheral nerve trauma. Mature neurotrophin-3 (NT3) protein is undetectable in the DRG under both normal and nerve trauma conditions. Genetic blockage of Nt3 mRNA/proNT3 protein upregulation in the injured DRG attenuates the development and maintenance of nerve trauma-induced neuropathic pain, without impacting acute/basal pain responses or locomotor function. Conversely, mimicking nerve trauma-induced upregulation of DRG Nt3 mRNA/pro-NT3 produces neuropathic pain-like symptoms. These symptoms are mitigated by intrathecal injection of NT3 protein or by selective knockdown of tropomyosin receptor kinase C (TrkC), but not TrkA or TrkB, in the DRG. Notably, intrathecal injection of NT3 also alleviates nerve trauma-induced neuropathic pain. Mechanistically, upregulated proNT3 contributes to the nerve trauma-induced increases of C-C chemokine ligand 2 (Ccl2) mRNA and CCL2 protein through activating TrkC in the injured DRG. Given that CCL2 is a key driver in neuropathic pain genesis and that Nt3 mRNA co-expresses with TrkC and Ccl2 mRNA in DRG neurons, proNT3 likely participates in nerve trauma-induced neuropathic pain through promoting TrkC-mediated increase of CCL2 in DRG neurons, highlighting a potential therapeutic target for the treatment of this disorder.