Pathological mechanism of musculoskeletal manifestations associated with CRPS type II: an animal study

Pain. 2014 Oct;155(10):1976-85. doi: 10.1016/j.pain.2014.06.016. Epub 2014 Jul 9.


Patients with complex regional pain syndrome (CRPS) often complain of abnormal sensations beyond the affected body part, but causes of this spread of musculoskeletal manifestations into contiguous areas remain unclear. In addition, immobilization can predispose to the development of CRPS. We examined functional, biochemical, and histological alterations in affected parts, including contiguous zones, using an animal model. Ten-week-old male Wistar rats were assigned to 5 groups: a normal group receiving no treatment, a sham operation group with surgical exploration, an immobilization group with surgical exploration plus internal knee joint immobilization, a surgical neuropathy group prepared by spinal nerve ligation (SNL) of the left L5 nerve root, and a surgical neuropathy+immobilization group with simultaneous SNL and knee joint immobilization. Mechanical allodynia and knee contracture were compared between groups, and tissues were harvested for histological assessments and gene and protein expression analyses. Neither surgical procedures nor immobilization induced detectable mechanical sensitivity. However, the addition of nerve injury resulted in detectable mechanical allodynia, and immobilization not only accelerated hyperalgesia, but also resulted in muscle fibrosis. Nerve growth factor (NGF) and other mediators of neurogenic inflammation were highly expressed not only in denervated muscles, but also in innervated muscles in contiguous areas, suggesting the spread of NGF production beyond the myotome of the injured nerve. Transforming growth factor β was involved in the development of contracture in CRPS. These findings imply that neuroinflammatory components play major roles in the progression and dispersion of both sensory pathologies and pathologies that are exacerbated by immobilization.

Keywords: Allodynia; Animal experiment; Complex regional pain syndrome; Contracture; Musculoskeletal manifestations; Pain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Causalgia / metabolism
  • Causalgia / pathology
  • Causalgia / physiopathology*
  • Cytokines / metabolism
  • Disease Models, Animal
  • Hyperalgesia / metabolism
  • Hyperalgesia / pathology
  • Hyperalgesia / physiopathology*
  • Immobilization
  • Inflammation Mediators / metabolism
  • Knee Joint / metabolism
  • Knee Joint / pathology
  • Knee Joint / physiopathology*
  • Male
  • Nerve Growth Factor / metabolism
  • Pain Measurement
  • Pain Threshold / physiology
  • Physical Stimulation
  • Rats
  • Rats, Wistar


  • Cytokines
  • Inflammation Mediators
  • Nerve Growth Factor