Pain mechanisms in osteoarthritis: recent discoveries and opportunities ahead.

Clinically meaningful therapeutics targeting osteoarthritis pain have remained elusive over the years, but the collective understanding of mechanisms driving joint pain has continued to progress, offering a hopeful future. Recent significant discoveries in the field include detailed characterizations of structural and functional neuroplasticity within the joint, highlighting the contributions of non-neuronal cells in mediating this neuroplasticity. Notably, nerve growth factor has been identified as an important mediator of nociceptor sensitization and is expressed by many cells in the OA joint ( chondrocytes, synovial fibroblasts, macrophages, osteoclasts). The release of pain-sensitizing mediators from non-neuronal cells is largely attributed to tissue damage and inflammation; however, the role of metabolism in OA pain development has begun to garner more attention and is discussed further in this narrative minireview. Altered whole-body and cellular metabolism can influence pain through various mechanisms, including adipokine hormonal signaling and metabolite production from catabolic pathways. The emerging potential of glucagon-like peptide-1 receptor agonists to treat osteoarthritis pain and possible mechanisms are discussed. Finally, the future of elucidating pain mechanisms and translational success will require novel experimental approaches and increased use of human tissue-based models, which are briefly discussed.