Ultrastructure of the synovial sensory peptidergic fibers is distinctively altered in different phases of adjuvant induced arthritis in rats: ultramorphological characterization combined with morphometric and immunohistochemical study for substance P, calcitonin gene related peptide, and protein gene product 9.5

J Rheumatol. 1997 Nov;24(11):2177-87.


Objective: To characterize sequential ultramorphological changes in synovial sensory peptidergic fibers in different phases of adjuvant induced arthritis.

Methods: Topographically defined regions of the tarsal joints from arthritic rats were evaluated 7, 10, 14, and 21 days after inoculation with Freund's adjuvant. Peptidergic fibers were identified by high resolution video microscope, then fibers containing calcitonin gene related peptide (CGRP) were visualized by electron microscopy. Morphometric quantification of synovial fibers immunohistochemically stained for CGRP, substance P (SP), and protein gene product 9.5 (PGP 9.5) was done at this time.

Results: The control synovial lining contained numerous ramified axon terminals, whereas the sublining contained mostly nerve fiber bundles, except for axon terminals visible around the blood vessels. In arthritis, on Day 14, there were few immunoreactive nerve fibers and terminals. Instead, electron microscopy disclosed numerous activated and/or degenerated axons [CGRP: 2973 +/- 345 vs 495 +/- 288; SP: 657 +/- 344 vs 199 +/- 60; PGP 9.5: 4473 +/- 944 vs 886 +/- 299, all p < 0.05 (units: microm/mm2)]. On Day 21 CGRP and PGP 9.5 immunoreactive fibers were numerous again (4892 +/- 551 and 3613 +/- 1350, respectively), but SP immunoreactive nerve fibers did not seem to regenerate (126 +/- 44). Regenerating nerve fibers had a distinctive ultrastructure and they were always seen in association to Schwann cells.

Conclusion: The healthy synovial lining is innervated by peptidergic nerve terminals. During the inflammatory phase of arthritis neuropeptides are locally released due to stimulation and degeneration of the axons. The apparently unaffected Schwann cells seem to play a pivotal role in subsequent regeneration of peptidergic axons. However, the ultrastructure and the neuropeptide content (and probably the function) of the regenerating axons are different from those of the normal synovial nerve fibers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Experimental / metabolism*
  • Arthritis, Experimental / pathology*
  • Calcitonin Gene-Related Peptide / analysis
  • Immunohistochemistry
  • Male
  • Microscopy, Electron
  • Microscopy, Immunoelectron
  • Nerve Tissue Proteins / analysis
  • Neurons, Afferent / chemistry
  • Neurons, Afferent / pathology*
  • Neurons, Afferent / ultrastructure
  • Neuropeptides / analysis*
  • Rats
  • Rats, Wistar
  • Substance P / analysis
  • Synovial Membrane / chemistry
  • Synovial Membrane / innervation*
  • Thiolester Hydrolases / analysis
  • Time Factors
  • Ubiquitin Thiolesterase


  • Nerve Tissue Proteins
  • Neuropeptides
  • Substance P
  • Thiolester Hydrolases
  • Ubiquitin Thiolesterase
  • Calcitonin Gene-Related Peptide