Beta-endorphin, Met-enkephalin and corresponding opioid receptors within synovium of patients with joint trauma, osteoarthritis and rheumatoid arthritis

Ann Rheum Dis. 2007 Jul;66(7):871-9. doi: 10.1136/ard.2006.067066. Epub 2007 Feb 26.


Objective: Intra-articularly applied opioid agonists or antagonists modulate pain after knee surgery and in chronic arthritis. Therefore, the expression of beta-endorphin (END), Met-enkephalin (ENK), and mu and delta opioid receptors (ORs) within synovium of patients with joint trauma (JT), osteoarthritis (OA) and rheumatoid arthritis (RA) were examined.

Methods: Synovial samples were subjected to double immunohistochemical analysis of opioid peptides with immune cell markers, and of ORs with the neuronal markers calcitonin gene-related peptide (CGRP) and tyrosine hydroxylase (TH).

Results: END and ENK were expressed by macrophage-like (CD68(+)) and fibroblast-like (CD68(-)) cells within synovial lining layers of all disorders. In the sublining layers, END and ENK were mostly expressed by granulocytes in patients with JT, and by macrophages/monocytes, lymphocytes and plasma cells in those with OA and RA. Overall, END- and ENK-immunoreactive (IR) cells were more abundant in patients with RA than in those with OA and JT. ORs were found on nerve fibres and immune cells in all patients. OR-IR nerve fibres were significantly more abundant in patients with RA than in those with OA and JT. muORs and deltaORs were coexpressed with CGRP but not with TH.

Conclusions: Parallel to the severity of inflammation, END and ENK in immune cells and their receptors on sensory nerve terminals are more abundant in patients with RA than in those with JT and OA. These findings are consistent with the notion that, with prolonged and enhanced inflammation, the immune and peripheral nervous systems upregulate sensory nerves expressing ORs and their ligands to counterbalance pain and inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Arthritis / immunology
  • Arthritis / metabolism*
  • Arthritis, Rheumatoid / immunology
  • Arthritis, Rheumatoid / metabolism
  • Biomarkers / analysis
  • Enkephalin, Methionine / analysis*
  • Female
  • Humans
  • Immunohistochemistry / methods
  • Joints / immunology
  • Joints / injuries*
  • Leukocytes / immunology
  • Male
  • Middle Aged
  • Osteoarthritis / immunology
  • Osteoarthritis / metabolism
  • Receptors, Opioid / analysis*
  • Receptors, Opioid, delta / analysis
  • Receptors, Opioid, mu / analysis
  • Synovial Membrane / chemistry*
  • Synovial Membrane / immunology
  • beta-Endorphin / analysis*


  • Biomarkers
  • Receptors, Opioid
  • Receptors, Opioid, delta
  • Receptors, Opioid, mu
  • Enkephalin, Methionine
  • beta-Endorphin