Evidence for neurogenic transmission inducing degenerative cartilage damage distant from local inflammation

Arthritis Rheum. 1999 Sep;42(9):1951-60. doi: 10.1002/1529-0131(199909)42:9<1951::AID-ANR22>3.0.CO;2-D.


Objective: To investigate involvement of the nervous system in ipsilateral and contralateral joint inflammation.

Methods: Freund's complete adjuvant (CFA; 1 mg or 1 microg) was injected unilaterally and the messages (a) from the hind paw to the ipsilateral and contralateral knees and (b) from one knee to the contralateral knee were analyzed. The degenerative impact of the local injury on distant cartilage was assessed using patellar proteoglycan synthesis as an indicator. Neurogenic mechanisms were blocked either by spinal cord compression or by injection of neurokinin 1 (NK-1) antagonist, or they were mimicked by intraarticular injection of substance P. The data were compared with those gathered in a model of systemic inflammation, characterized by fever and serum interleukin-6 production.

Results: After unilateral subcutaneous injection of CFA, proteoglycan anabolism decreased bilaterally. Spinal cord compression and administration of the NK-1 antagonist inhibited the response in the contralateral limb. Following 1 mg CFA subcutaneous injection, the ipsilateral response implicated both neurogenic and systemic mechanisms, whereas the nervous system alone was implicated after 1 microg subcutaneous CFA injection. The 1 microg CFA intraarticular injection induced a degenerative contralateral signal, which was abolished by spinal cord compression and by pretreatment with the NK-1 antagonist. Intraarticular injection of 1 microg CFA also induced an ipsilateral increase of anabolism, which was enhanced by spinal cord compression. Similar results were obtained after intraarticular injections of substance P. These effects were not reproduced with turpentine treatment, a systemic model, in which spinal cord compression had no effect.

Conclusion: A unilateral inflammation can induce, by neurogenic mechanisms, distal bilateral degeneration of articular cartilage, implicating involvement of neuropeptides.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Rheumatoid / etiology*
  • Freund's Adjuvant / administration & dosage
  • Injections, Intra-Articular
  • Injections, Subcutaneous
  • Interleukin-6 / blood
  • Knee Joint
  • Male
  • Neurokinin-1 Receptor Antagonists
  • Prostaglandins / metabolism
  • Rats
  • Rats, Wistar
  • Substance P / administration & dosage
  • Synaptic Transmission / physiology*
  • Turpentine / administration & dosage


  • Interleukin-6
  • Neurokinin-1 Receptor Antagonists
  • Prostaglandins
  • Substance P
  • Freund's Adjuvant
  • Turpentine