The First Scintigraphic Detection of Tumor Necrosis Factor-Alpha in Patients with Complex Regional Pain Syndrome Type 1

Bernateck, Michael; Karst, Matthias; Gratz, K. F.; Meyer, Geerd J.; Fischer, Michael J.; Knapp, Wolfram H.; Koppert, Wolfgang; Brunkhorst, Thomas

doi:10.1213/ane.0b013e3181c4bab7

Cited by 22 publications

(15 citation statements)

References 17 publications

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“…Intriguingly, inflammatory cytokines such as TNF-α and IL-6 are up-regulated in CRPS skin and skin blister fluid. 2, 17, 19, 20, 23 Recently we observed that in patients with early CRPS there is keratinocyte proliferation in the affected skin and these activated keratinocytes express TNF-α and IL-6. 4 Similarly, at 4 weeks after fracture/casting in rats the hindpaw skin keratinocytes proliferate and express increased levels of TNF-α, IL-1β, IL-6, and NGF in the hindpaw skin.…”

Section: Discussionmentioning

confidence: 99%

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

Guo

Wei

et al. 2014

The Journal of Pain

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A tibia fracture cast immobilized for 4 weeks can induce exaggerated substance P (SP) and CGRP signaling and neuropeptide-dependent nociceptive and inflammatory changes in the hindlimbs of rats similar to those seen in complex regional pain syndrome (CRPS). Four weeks of hindlimb 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 hindlimb casted, 3) hindlimb casted, no fracture, 4) tibia fracture with intrameduallary pinning, no cast, and 5) tibia fracture with intrameduallary pinning and hindlimb casting. After 4 weeks the casts were removed and hindlimb 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 SP and CGRP, increased skin NK1 receptors and keratinocyte proliferation, increased in inflammatory mediator expression in the hindpaw skin (TNF-α, IL-1β, IL-6, NGF) and cord (IL-1β, NGF), and increased spinal c-Fos activation. These same changes were observed after cast immobilization alone, except spinal IL-1β levels were not increased. Treating cast only rats with an NK1 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.

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Section: Discussionmentioning

confidence: 99%

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

Guo

Wei

et al. 2014

The Journal of Pain

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“…21 Furthermore, TNF-α levels are increased in CRPS skin biopsies when measured by enzyme immunoassay and in CRPS affected hands scintigraphically imaged with radiolabeled anti-TNF-α antibody. 1, 24 …”

Section: Introductionmentioning

confidence: 99%

Activation of Cutaneous Immune Responses in Complex Regional Pain Syndrome

Birklein

Drummond

et al. 2014

The Journal of Pain

114

109

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The pathogenesis of complex regional pain syndrome (CRPS) is unresolved, but TNF-α and IL-6 are elevated in experimental skin blister fluid from CRPS affected limbs, as is tryptase, a marker for mast cells. In the rat fracture model of CRPS exaggerated sensory and sympathetic neural signaling stimulate keratinocyte and mast cell proliferation, causing the local production of high levels of inflammatory cytokines leading to pain behavior. The current investigation used CRPS patient skin biopsies to determine whether keratinocyte and mast cell proliferation occur in CRPS skin and to identify the cellular source of the up-regulated TNF-α, IL-6, and tryptase observed in CRPS experimental skin blister fluid. Skin biopsies were collected from the affected skin and the contralateral mirror site in 55 CRPS patients and the biopsy sections were immunostained for keratinocyte, cell proliferation, mast cell markers, TNF-α, and IL-6. In early CRPS keratinocytes were activated in the affected skin, resulting in proliferation, epidermal thickening, and up-regulated TNF-α and IL-6 expression. In chronic CRPS there was reduced keratinocyte proliferation with epidermal thinning in the affected skin. Acute CRPS patients also had increased mast cell accumulation in the affected skin, but there was no increase in mast cell numbers in chronic CRPS.

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“…These depolarizations trigger the release of neuropeptides such as CGRP and substance P (SP), which induce local inflammation, protein extravasation, vasodilatation, and the release of cytokines [18]. Accordingly, skin levels of SP, CGRP, and inflammatory cytokines are elevated in CRPS [2,20,23,28]. Tissue hypoxia in itself may also elicit inflammation by up-regulating nuclear factor-jB transcription [47].…”

Section: Inflammation and Edema In Crpsmentioning

confidence: 99%

Capillary dysfunction and impaired tissue oxygenation in complex regional pain syndrome: A hypothesis

Østergaard

Terkelsen

Finnerup

et al. 2014

Pain

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The First Scintigraphic Detection of Tumor Necrosis Factor-Alpha in Patients with Complex Regional Pain Syndrome Type 1

Cited by 22 publications

References 17 publications

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

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

Activation of Cutaneous Immune Responses in Complex Regional Pain Syndrome

Capillary dysfunction and impaired tissue oxygenation in complex regional pain syndrome: A hypothesis

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