Substance P signaling contributes to the vascular and nociceptive abnormalities observed in a tibial fracture rat model of complex regional pain syndrome type I

Pain. 2004 Mar;108(1-2):95-107. doi: 10.1016/j.pain.2003.12.010.


Wrist and ankle fractures are the most frequent causes of complex regional pain syndrome (CRPS type I). The current study examined the temporal development of vascular, nociceptive and bony changes after distal tibial fracture in rats and compared these changes to those observed after cast immobilization in intact normal rats. After baseline testing the right distal tibial was fractured and the hindlimb casted. A control group was simply casted without fracturing the tibia. After 4 weeks the casts were removed and the rats retested. Subsequent testing was performed at 6, 8, 10, 16, and 20 weeks after onset of treatment. Distal tibial fracture or cast immobilization alone generated chronic hindlimb warmth, edema, spontaneous protein extravasation, allodynia, and periarticular osteoporosis, changes resembling those observed in CRPS. Hindlimb warmth and allodynia resolved much more quickly after cast immobilization than after fracture. Previously we observed that the substance P receptor (NK(1)) antagonist LY303870 reversed vascular and nociceptive changes in a sciatic section rat model of CRPS type II. Postulating that facilitated substance P signaling may also contribute to the vascular and nociceptive abnormalities observed after tibial fracture or cast immobilization, we attempted to reverse these changes with LY303870. Hindpaw warmth, spontaneous extravasation, edema, and allodynia were inhibited by LY303870. Collectively, these data support the hypotheses that the distal tibial fracture model simulates CRPS, immobilization alone can generate a syndrome resembling CRPS, and substance P signaling contributes to the vascular and nociceptive changes observed in these models.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Body Temperature
  • Bone Diseases, Metabolic / etiology
  • Bone Diseases, Metabolic / physiopathology
  • Casts, Surgical
  • Disease Models, Animal
  • Edema / physiopathology
  • Hindlimb
  • Indoles / pharmacology
  • Male
  • Nociceptors / drug effects
  • Nociceptors / physiology*
  • Piperidines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Reflex Sympathetic Dystrophy / etiology*
  • Reflex Sympathetic Dystrophy / physiopathology*
  • Signal Transduction / physiology
  • Substance P / physiology*
  • Tibial Fractures / complications*
  • Tibial Fractures / therapy


  • 1-(N-(2-methoxybenzyl)acetylamino)-3-(1H-indol-3-yl)-2-(N-(2-(4-(piperidin-1-yl)piperidin-1-yl)acetyl)amino)propane
  • Indoles
  • Piperidines
  • Substance P