Neuropathic pain remains an area of considerable unmet medical need. A persistent
challenge in the management of neuropathic pain is to target the specific mechanisms
leading to a change from normal to abnormal sensory perception while ensuring that
the defensive pain perception remains intact. Targeting VGF-derived neuropeptides
may offer this opportunity. VGF was first identified in 1985 and is highly expressed
following nerve injury and inflammation in neurons of both the peripheral and central
nervous system. Subsequent studies implicate the vgf gene and its products in pain
pathways. This narrative review was supported by a systematic search to identify,
select and critically appraise all relevant research investigating the role of VGF-derived
neuropeptides in pain pathways. It predominantly focuses on in vivo investigations of
the role of VGF in the initiation and maintenance of neuropathic pain. VGF expression
levels are very low under normal physiological conditions and nerve injury results in
rapid and robust upregulation, increasing mechanical and thermal hypersensitivity.
The identification of the two complement receptors with which VGF-neuropeptides
interact suggests a novel interplay of neuronal and immune signalling mediators. The
understanding of the molecular mechanisms and signalling events by which VGFderived
active neuropeptides exert their physiological actions is in its infancy. Future
work should aim to improve understanding of the downstream consequences of VGFneuropeptides
thereby providing novel insights into pain mechanisms potentially
leading to the identification of novel therapeutic targets.