EXPRESS: Precursor signaling redefined: proneurotrophin-3, not neurotrophin-3, in primary sensory neurons as an instigator in neuropathic pain

Neurotrophin-3 (NT3), one member of the nerve growth factor family of neurotrophins, is initially synthesized as a large precursor, termed proneurotrophin-3 (proNT3), which undergoes proteolytic cleavage to generate mature NT3. A growing body of evidence suggests that proNT3 and its mature form, NT3, have opposing roles in the nervous system. A systematic literature search of PubMed was conducted using predefined search terms related to NT3, proNT3, expression, dorsal root ganglion (DRG) and pain. The role of NT3 in neuropathic pain has been debated in earlier studies. Importantly, more recent studies have shown that proNT3, rather than NT3, is expressed in the DRG. In this review, we delineate the expression and distribution pattern of proNT3 in primary sensory neurons of the DRG under normal conditions, as well as its upregulation in injured DRG following peripheral nerve injury. We highlight that DRG proNT3 upregulation is required for the development and maintenance of neuropathic pain and discuss the role of C-C chemokine ligand 2 in mediating the contribution of proNT3-triggered TrkC activation to neuropathic pain in the DRG.