Neuropeptide deficient mice have attenuated nociceptive, vascular, and inflammatory changes in a tibia fracture model of complex regionalpain syndrome

Molecular Pain

Wade S Kingery²  David J Clark³  Kejun Cheng⁴  Kenner C Rice⁴  Kazutake Tsujikawa¹  Liping Wang²  Saiyun Hou²  Wen-Wu Li³  Xiaoyou Shi³  Tzuping Wei²  Tian-Zhi Guo² 

[1] Department of Immunology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan;Physical Medicine and Rehabilitation Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA;Department of Anesthesiolgy, Stanford University School of Medicine, Stanford, CA, USA;Drug Design and Synthesis Section, Chemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA

关键词: Nerve growth factor;    Cytokine;    Pain;    Inflammation;    Complex regional pain syndrome;    Fracture;    Calcitonin gene-related peptide;    Substance P;   

Others  :  863319
DOI  :  10.1186/1744-8069-8-85

 received in 2012-08-26, accepted in 2012-11-21,  发布年份 2012

【 摘 要 】

Background

Distal limb fracture in man can induce a complex regional pain syndrome (CRPS) with pain, warmth, edema, and cutaneous inflammation. In the present study substance P (SP, Tac1^−/−) and CGRP receptor (RAMP1^−/−) deficient mice were used to investigate the contribution of neuropeptide signaling to CRPS-like changes in a tibia fracture mouse model. Wildtype, Tac1^−/−, and RAMP1^−/− mice underwent tibia fracture and casting for 3 weeks, then the cast was removed and hindpaw mechanical allodynia, unweighting, warmth, and edema were tested over time. Hindpaw skin was collected at 3 weeks post-fracture for immunoassay and femurs were collected for micro-CT analysis.

Results

Wildtype mice developed hindpaw allodynia, unweighting, warmth, and edema at 3 weeks post-fracture, but in the Tac1^−/− fracture mice allodynia and unweighting were attenuated and there was no warmth and edema. RAMP1^−/− fracture mice had a similar presentation, except there was no reduction in hindpaw edema. Hindpaw skin TNFα, IL-1β, IL-6 and NGF levels were up-regulated in wildtype fracture mice at 3 weeks post-fracture, but in the Tac1^−/− and RAMP1^−/− fracture mice only IL-6 was increased. The epidermal keratinocytes were the cellular source for these inflammatory mediators. An IL-6 receptor antagonist partially reversed post-fracture pain behaviors in wildtype mice.

Conclusions

In conclusion, both SP and CGRP are critical neuropeptide mediators for the pain behaviors, vascular abnormalities, and up-regulated innate immune responses observed in the fracture hindlimb. We postulate that the residual pain behaviors observed in the Tac1^−/− and RAMP1^−/− fracture mice are attributable to the increased IL-6 levels observed in the hindpaw skin after fracture.

【 授权许可】

   
2012 Guo et al.; licensee BioMed Central Ltd.

【 图 表 】

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