Highlights
- •Tibia fracture with 4 weeks cast immobilization induced CRPS-like changes in rats.
- •Four weeks of cast immobilization (with no fracture) induced CRPS-like changes.
- •Early mobilization after fracture inhibited development of CRPS-like changes.
- •Early limb mobilization after fracture may prevent the development of CRPS in humans.
Abstract
A tibia fracture cast immobilized for 4 weeks can induce exaggerated substance P and
calcitonin gene–related peptide signaling and neuropeptide-dependent nociceptive and
inflammatory changes in the hind limbs of rats similar to those seen in complex regional
pain syndrome (CRPS). Four weeks of hind limb cast immobilization can also induce
nociceptive and vascular changes resembling CRPS. To test our hypothesis that immobilization
alone could cause exaggerated neuropeptide signaling and inflammatory changes, we
tested 5 cohorts of rats: 1) controls; 2) tibia fracture and hind limb casted; 3)
hind limb casted, no fracture; 4) tibia fracture with intramedullary pinning, no cast;
and 5) tibia fracture with intramedullary pinning and hind limb casting. After 4 weeks,
the casts were removed and hind limb allodynia, unweighting, warmth, edema, sciatic
nerve neuropeptide content, cutaneous and spinal cord inflammatory mediator levels,
and spinal c-Fos activation were measured. After fracture with casting, there was
allodynia, unweighting, warmth, edema, increased sciatic nerve substance P and calcitonin
gene–related peptide, increased skin neurokinin 1 receptors and keratinocyte proliferation,
increased inflammatory mediator expression in the hind paw skin (tumor necrosis factor-α,
interleukin [IL]-1β, IL-6, nerve growth factor) and cord (IL-1β, nerve growth factor),
and increased spinal c-Fos activation. These same changes were observed after cast
immobilization alone, except that spinal IL-1β levels were not increased. Treating
cast-only rats with a neurokinin 1 receptor antagonist inhibited development of nociceptive
and inflammatory changes. Four weeks after fracture with pinning, all nociceptive
and vascular changes had resolved and there were no increases in neuropeptide signaling
or inflammatory mediator expression.
Perspective
Collectively, these data indicate that immobilization alone increased neuropeptide
signaling and caused nociceptive and inflammatory changes similar to those observed
after tibia fracture and casting, and that early mobilization after fracture with
pinning inhibited these changes. Early limb mobilization after fracture may prevent
the development of CRPS.
Key words
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Article info
Publication history
Published online: July 22, 2014
Accepted:
July 6,
2014
Received in revised form:
June 20,
2014
Received:
March 25,
2014
Footnotes
This study was funded by National Institutes of Health grant NS072168, Department of Veterans Affairs Rehabilitation Research and Development Merit grant F7137R.
The authors do not have any financial or other relationships that might lead to conflicts of interest.
Identification
Copyright
Published by Elsevier Inc.
