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

Abstract

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.

Effect of anti-NGF antibodies in a rat tibia fracture model of complex regional pain syndrome type I

“…Tibia fracture was performed under isoflurane anesthesia as we have previously described (Guo et al 2004). The right hindlimb was wrapped in stockinet (2.5 cm wide) and the distal tibia was fractured using pliers with an adjustable stop that had been modified with a 3-point jaw.…”

“…To measure mechanical allodynia in the rats an up-down von Frey testing paradigm was used as we have previously described (Kingery et al 2003;Guo et al 2004;Guo et al 2006). Rats were placed in a clear plastic cylinder (20 cm in diameter) with a wire mesh bottom and allowed to acclimate for 15 minutes.…”

“…A laser sensor technique was used to determine the dorsal-ventral thickness of the hindpaw, as we have previously described (Kingery et al 2003;Guo et al 2004;Guo et al 2006). Before baseline testing the bilateral hindpaws were tattooed with a 2-3 mm spot on the dorsal skin over the midpoint of the third metatarsal.…”

“…This model exhibits the classical signs of CRPS type I including allodynia, edema, warmth, and periarticular bone loss. There is also facilitated substance P (SP) signaling in the injured limb of this model (Guo et al 2004;Guo et al 2006) and in CRPS patients (Weber et al 2001;Leis et al 2003). Excessive SP signaling can directly induce keratinocyte nerve growth factor (NGF) expression and increase NGF levels in the skin of rodents (Amann et al 2000;Burbach et al 2001;Amann and Schuligoi 2004).…”

“…Many CRPS patients experience chronic pain and disability (Geertzen et al 2006;Vaneker et al 2006). Our group recently developed a model of CRPS (type I) based on distal tibial fracture and cast immobilization in rats (Guo et al 2004). This model exhibits the classical signs of CRPS type I including allodynia, edema, warmth, and periarticular bone loss.…”