Arthritis is the commonest cause of disabling
chronic pain, and both
osteoarthritis (OA) and
rheumatoid arthritis (RA) remain major burdens on both individuals and society. Peripheral release of
calcitonin gene-related peptide (CGRP) contributes to the vasodilation of acute
neurogenic inflammation. Contributions of CGRP to the
pain and
inflammation of chronic
arthritis, however, are only recently being elucidated. Animal models of
arthritis are revealing the molecular and pathophysiological events that accompany and lead to progression of both
arthritis and
pain. Peripheral actions of CGRP in the joint might contribute to both
inflammation and joint afferent sensitization. CGRP and its specific receptors are expressed in joint afferents and up-regulated following
arthritis induction. Peripheral CGRP release results in activation of synovial vascular cells, through which acute vasodilatation is followed by endothelial cell proliferation and angiogenesis, key features of chronic
inflammation. Local administration of CGRP to the knee also increases mechanosensitivity of joint afferents, mimicking peripheral sensitization seen in arthritic joints. Increased mechanosensitivity in OA knees and
pain behaviour can be reduced by peripherally acting
CGRP receptor antagonists. Effects of CGRP pathway blockade on arthritic joint afferents, but not in normal joints, suggest contributions to sensitization rather than normal joint nociception. CGRP therefore might make key contributions to the transition from normal to persistent
synovitis, and the progression from nociception to sensitization. Targeting CGRP or its receptors within joint tissues to prevent these undesirable transitions during early
arthritis, or suppress them in established disease, might prevent persistent
inflammation and relieve
arthritis pain.