Emerging evidence of artemin/GFRα3 signaling in musculoskeletal pain

Chronic musculoskeletal pain is highly prevalent and poses a significant personal, societal, and economic burden. Management of chronic musculoskeletal pain remains a challenge. Long-term use of common analgesic medications such as nonsteroidal anti-inflammatory drugs and opioids is associated with adverse events, and in the case of opioids, drug addiction. Additionally, many individuals do not experience sufficient pain relief with these therapeutic approaches. Thus, there is an urgent need to develop clinically efficacious and safe therapeutics for musculoskeletal pain. Recent advances in our understanding of musculoskeletal pain neurobiology have helped identify the role of neurotrophic factors, specifically, the glial cell line-derived neurotrophic factor (GDNF) family of ligands (GFL) and their associated signaling pathways. This review outlines our current understanding of the GFL signaling systems, discusses their role in inflammatory and chronic musculoskeletal pain and sensitivity, and comments on the analgesic therapeutic potential of targeting the GFL signaling system.