title: Neuropeptide deficient mice have attenuated nociceptive, vascular, and inflammatory changes in a tibia fracture model of complex regional  pain syndrome.
abstract: 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.
authors.affiliation: Physical Medicine and Rehabilitation Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA.
authors.forename: Tian-Zhi
authors.initials: TZ
authors.lastname: Guo
authors.forename: Tzuping
authors.initials: T
authors.lastname: Wei
authors.forename: Xiaoyou
authors.initials: X
authors.lastname: Shi
authors.forename: Wen-Wu
authors.initials: WW
authors.lastname: Li
authors.forename: Saiyun
authors.initials: S
authors.lastname: Hou
authors.forename: Liping
authors.initials: L
authors.lastname: Wang
authors.forename: Kazutake
authors.initials: K
authors.lastname: Tsujikawa
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
authors.forename: Kejun
authors.initials: K
authors.lastname: Cheng
authors.forename: David J
authors.initials: DJ
authors.lastname: Clark
authors.forename: Wade S
authors.initials: WS
authors.lastname: Kingery
mesh_terms: D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000235:genetics / Q000378:metabolism; D020918:Complex Regional Pain Syndromes / Q000235:genetics / Q000378:metabolism*; D006930:Hyperalgesia / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D010146:Pain / Q000235:genetics / Q000378:metabolism*; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000235:genetics / Q000378:metabolism; D013978:Tibial Fractures / Q000235:genetics / Q000378:metabolism*
chemical_list: D009479:Neuropeptides; D018015:Receptors, Calcitonin Gene-Related Peptide; D020932:Nerve Growth Factor; D015740:Calcitonin Gene-Related Peptide