Calcitonin gene-related peptide in the joint: contributions to pain and inflammation

Br J Clin Pharmacol. 2015 Nov;80(5):965-78. doi: 10.1111/bcp.12669. Epub 2015 Jul 22.

Abstract

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.

Keywords: Calcitonin gene-related peptide; inflammation; joints; pain.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Calcitonin Gene-Related Peptide / metabolism*
  • Calcitonin Gene-Related Peptide Receptor Antagonists
  • Disease Models, Animal
  • Endothelial Cells / physiology
  • Humans
  • Inflammation / metabolism
  • Inflammation / physiopathology*
  • Joints / metabolism
  • Joints / physiopathology*
  • Models, Biological
  • Neovascularization, Pathologic / physiopathology
  • Pain / metabolism
  • Pain / physiopathology*

Substances

  • Calcitonin Gene-Related Peptide Receptor Antagonists
  • Calcitonin Gene-Related Peptide