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Keratinocyte expression of inflammatory mediators plays a crucial role in substance P-induced acute and chronic pain

Tzuping Wei1, Tian-Zhi Guo1, Wen-Wu Li123, Saiyun Hou1, Wade S Kingery1 and John David Clark23*

Author Affiliations

1 Physical Medicine and Rehabilitation Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA94304, USA

2 Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue (112-A), Palo Alto, CA94304, USA

3 Department of Anesthesiolgy, Stanford University School of Medicine, Stanford, CA94304, USA

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Journal of Neuroinflammation 2012, 9:181  doi:10.1186/1742-2094-9-181

Published: 23 July 2012


Tibia fracture in rats followed by cast immobilization leads to nociceptive, trophic, vascular and bone-related changes similar to those seen in Complex Regional Pain Syndrome (CRPS). Substance P (SP) mediated neurogenic inflammation may be responsible for some of the signs of CRPS in humans. We therefore hypothesized that SP acting through the SP receptor (NK1) leads to the CRPS-like changes found in the rat model. In the present study, we intradermally injected rats with SP and monitored hindpaw mechanical allodynia, temperature, and thickness as well as tissue levels of tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β), interleukin 6 (IL-6), and nerve growth factor-β (NGF) for 72 h. Anti-NGF antibody was utilized to block the effects of SP-induced NGF up-regulation. Fracture rats treated with the selective NK1 receptor antagonist LY303870 prior to cast removal were assessed for BrdU, a DNA synthesis marker, incorporation in skin cells to examine cellular proliferation. Bone microarchitecture was measured using micro computed tomography (μCT). We observed that: (1) SP intraplantar injection induced mechanical allodynia, warmth and edema as well as the expression of nociceptive mediators in the hindpaw skin of normal rats, (2) LY303870 administered intraperitoneally after fracture attenuated allodynia, hindpaw unweighting, warmth, and edema, as well as cytokine and NGF expression, (3) LY303870 blocked fracture-induced epidermal thickening and BrdU incorporation after fracture, (4) anti-NGF antibody blocked SP-induced allodynia but not warmth or edema, and (5) LY303870 had no effect on bone microarchitecture. Collectively our data indicate that SP acting through NK1 receptors supports the nociceptive and vascular components of CRPS, but not the bone-related changes.