Oxidative Stress Contributes to Fracture/Cast-Induced Inflammation and Pain in a Rat Model of Complex Regional Pain Syndrome

J Pain. 2018 Oct;19(10):1147-1156. doi: 10.1016/j.jpain.2018.04.006. Epub 2018 Apr 30.


Clinical evidence suggests that vitamin C (Vit C) may protect against the development of complex regional pain syndrome (CRPS) after fracture or surgery. Tibia fracture followed by 4 weeks of cast immobilization (fracture/cast) in rats results in nociceptive, vascular, and bone changes resembling clinical CRPS. In this study, fracture/cast rats were treated with the oxidative stress inhibitors Vit C, N-acetyl cysteine, or 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl to examine their effects on CRPS-related nociceptive and vascular changes. Administration of these agents significantly reduced fracture/cast-induced cutaneous allodynia by 64 to 78%, muscle hyperalgesia by 34 to 40%, and hind limb unweighting by 48 to 89%. Treatments with Vit C and N-acetyl cysteine reduced the oxidative stress markers malondialdehyde in the skin, muscle, and sciatic nerve, and lactate in the gastrocnemius muscle of the fracture/cast limb. Furthermore, Vit C treatment inhibited the post-fracture upregulation of substance P and calcitonin gene-related peptide in the sciatic nerve and the increased expression of the pain-related inflammatory mediators, including interleukin (IL)-6, and nerve growth factor in the skin and IL-1β, and IL-6 in the muscle of the post-fracture/cast limb. These data suggest that oxidative stress may contribute to the nociceptive features of the rat CRPS model.

Perspective: Vit C reduced the CRPS-like signs, oxidative stress, and the upregulation of neuropeptide production and inflammatory mediators observed after tibia fracture and casting in rats. Limiting oxidative stress by use of Vit C or alternative strategies could reduce the risk of developing CRPS after surgery or other forms of trauma.

Keywords: Fracture; complex regional pain syndrome; cytokines; immobilization.; oxidative stress; vitamin C.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antioxidants / pharmacology
  • Casts, Surgical
  • Complex Regional Pain Syndromes / etiology
  • Complex Regional Pain Syndromes / physiopathology*
  • Disease Models, Animal
  • Immobilization / adverse effects
  • Immobilization / methods
  • Inflammation / etiology
  • Inflammation / physiopathology*
  • Male
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology*
  • Pain / etiology
  • Pain / physiopathology*
  • Rats
  • Rats, Sprague-Dawley
  • Tibial Fractures / complications
  • Tibial Fractures / physiopathology*


  • Antioxidants