Neuropeptide deficient mice have attenuated nociceptive, vascular, and inflammatory changes in a tibia fracture model of complex regional pain syndrome
Tian-Zhi Guo (email@example.com)
Tzuping Wei (firstname.lastname@example.org)
Xiaoyou Shi (email@example.com)
Wen-Wu Li (firstname.lastname@example.org)
Saiyun Hou (email@example.com)
Liping Wang (firstname.lastname@example.org)
Kazutake Tsujikawa (email@example.com)
Kenner C Rice (firstname.lastname@example.org)
Kejun Cheng (email@example.com)
David J Clark (David.Clark5@va.gov)
Wade S Kingery (firstname.lastname@example.org)
Molecular Pain 2012, 8:85 doi:10.1186/1744-8069-8-85
Published: 28 November 2012
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.
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 TNFalpha, IL-1beta, 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.
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.
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