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Immobilization Contributes to Exaggerated Neuropeptide Signaling, Inflammatory Changes, and Nociceptive Sensitization After Fracture in Rats

  • Tian-Zhi Guo
    Affiliations
    Physical Medicine and Rehabilitation Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, California
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  • Tzuping Wei
    Affiliations
    Physical Medicine and Rehabilitation Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, California
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  • Wen-Wu Li
    Affiliations
    Physical Medicine and Rehabilitation Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, California

    Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, California

    Department of Anesthesiology, Stanford University School of Medicine, Stanford, California
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  • Xiang-Qi Li
    Affiliations
    Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, California

    Department of Anesthesiology, Stanford University School of Medicine, Stanford, California
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  • J. David Clark
    Affiliations
    Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, California

    Department of Anesthesiology, Stanford University School of Medicine, Stanford, California
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  • Wade S. Kingery
    Correspondence
    Address reprint requests to Wade S. Kingery, MD, PMRS (117), Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA 94304.
    Affiliations
    Physical Medicine and Rehabilitation Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, California
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      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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