title: Acute versus chronic phase mechanisms in a rat model of CRPS.
abstract: BACKGROUND
  Tibia fracture followed by cast immobilization in rats evokes nociceptive, vascular, epidermal, and bone changes resembling complex regional pain syndrome (CRPS). In most cases, CRPS has three stages. Over time, this acute picture, allodynia, warmth, and edema observed at 4 weeks, gives way to a cold, dystrophic but still painful limb. In the acute phase (at 4 weeks post fracture), cutaneous immunological and NK1-receptor signaling mechanisms underlying CRPS have been discovered; however, the mechanisms responsible for the chronic phase are still unknown. The purpose of this study is to understand the mechanisms responsible for the chronic phases of CRPS (at 16 weeks post fracture) at both the peripheral and central levels.
  
  
  METHODS
  We used rat tibial fracture/cast immobilization model of CRPS to study molecular, vascular, and nociceptive changes at 4 and 16 weeks post fracture. Immunoassays and Western blotting were carried out to monitor changes in inflammatory response and NK1-receptor signaling in the skin and spinal cord. Skin temperature and thickness were measured to elucidate vascular changes, whereas von Frey testing and unweighting were carried out to study nociceptive changes. All data were analyzed by one-way analysis of variance (ANOVA) followed by Neuman-Keuls multiple comparison test to compare among all cohorts.
  
  
  RESULTS
  In the acute phase (at 4 weeks post fracture), hindpaw allodynia, unweighting, warmth, edema, and/or epidermal thickening were observed among 90 % fracture rats, though by 16 weeks (chronic phase), only the nociceptive changes persisted. The expression of the neuropeptide signaling molecule substance P (SP), NK1 receptor, inflammatory mediators TNFα, IL-1β, and IL-6 and nerve growth factor (NGF) were elevated at 4 weeks in sciatic nerve and/or skin, returning to normal levels by 16 weeks post fracture. The systemic administration of a peripherally restricted IL-1 receptor antagonist (anakinra) or of anti-NGF inhibited nociceptive behaviors at 4 weeks but not 16 weeks. However, spinal levels of NK1 receptor, TNFα, IL-1β, and NGF were elevated at 4 and 16 weeks, and intrathecal injection of an NK1-receptor antagonist (LY303870), anakinra, or anti-NGF each reduced nociceptive behaviors at both 4 and 16 weeks.
  
  
  CONCLUSIONS
  These results demonstrate that tibia fracture and immobilization cause peripheral changes in neuropeptide signaling and inflammatory mediator production acutely, but central spinal changes may be more important for the persistent nociceptive changes in this CRPS model.
authors.affiliation: Physical Medicine and Rehabilitation Service, (RM A-132), Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA, 94304, USA. tzupingwei@yahoo.com.
authors.forename: Tzuping
authors.initials: T
authors.lastname: Wei
authors.affiliation: Physical Medicine and Rehabilitation Service, (RM A-132), Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA, 94304, USA. wxtguo@yahoo.com.
authors.forename: Tian-Zhi
authors.initials: TZ
authors.lastname: Guo
authors.affiliation: Physical Medicine and Rehabilitation Service, (RM A-132), Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA, 94304, USA. wenwu.li@gmail.com.
authors.forename: Wen-Wu
authors.initials: WW
authors.lastname: Li
authors.affiliation: Physical Medicine and Rehabilitation Service, (RM A-132), Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA, 94304, USA. wkingery@stanford.edu.
authors.forename: Wade S
authors.initials: WS
authors.lastname: Kingery
authors.affiliation: Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue (112-A), Palo Alto, CA, 94304, USA. djclark@stanford.edu.|Department of Anesthesiology, Stanford University School of Medicine, Stanford, CA, 94304, USA. djclark@stanford.edu.
authors.forename: John David
authors.initials: JD
authors.lastname: Clark
mesh_terms: D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001831:Body Temperature; D020918:Complex Regional Pain Syndromes / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology*; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D006614:Hindlimb / Q000473:pathology / Q000503:physiopathology; D007211:Indoles / Q000627:therapeutic use; D053590:Interleukin 1 Receptor Antagonist Protein / Q000627:therapeutic use; D008297:Male; D020932:Nerve Growth Factor / Q000276:immunology / Q000378:metabolism; D064729:Neurokinin-1 Receptor Antagonists / Q000627:therapeutic use; D059225:Nociception / Q000502:physiology; D010880:Piperidines / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D012584:Sciatic Nerve / Q000378:metabolism / Q000473:pathology; D013373:Substance P / Q000378:metabolism; D013978:Tibial Fractures / Q000150:complications; D013997:Time Factors
chemical_list: C096759:1-(N-(2-methoxybenzyl)acetylamino)-3-(1H-indol-3-yl)-2-(N-(2-(4-(piperidin-1-yl)piperidin-1-yl)acetyl)amino)propane; D000906:Antibodies; D018501:Antirheumatic Agents; D016207:Cytokines; D007211:Indoles; D053590:Interleukin 1 Receptor Antagonist Protein; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D013373:Substance P; D020932:Nerve Growth Factor