title: Substance P signaling controls mast cell activation, degranulation, and nociceptive sensitization in a rat fracture model of complex regional pain syndrome.
abstract: BACKGROUND
  Patients with complex regional pain syndrome have increased tryptase in the skin of the affected extremity indicating mast cell (MC) accumulation and degranulation, processes known to be mediated by substance P (SP). The dysregulation of SP release from primary afferent neurons is characteristic of complex regional pain syndrome. The authors hypothesized that SP acting through the neurokinin-1 receptor results in mast cell accumulation, degranulation, and nociceptive sensitization in a rat model of complex regional pain syndrome.
  
  
  METHODS
  Groups of 6-10 rats underwent tibia fracture and hind limb casting for 4 weeks, and the hind paw skin was harvested for histologic and immunohistochemical analysis. The effects of a selective neurokinin-1 receptor antagonist (LY303870) and of direct SP intraplantar injection were measured. Dermal MC degranulation induced by sciatic nerve stimulation and the effects of LY303870 on this process were investigated. Finally, the antinociceptive effects of acute and chronic treatment with a MC degranulator (48/80) were tested.
  
  
  RESULTS
  The authors observed that fracture caused MC accumulation, activation, and degranulation, which were inhibited by LY303870; the percentage of MCs in close proximity to peptidergic nerve fibers increased after fracture; electrical stimulation caused MC activation and degranulation, which was blocked by LY303870; intraplantar SP-induced MC degranulation and acute administration of 48/80 caused MC degranulation and enhanced postfracture nociception, but MC-depleted animals showed less sensitization.
  
  
  CONCLUSIONS
  These results indicate that facilitated peptidergic neuron-MC signaling after fracture can cause MC accumulation, activation, and degranulation in the injured limb, resulting in nociceptive sensitization.
authors.affiliation: Physical Medicine and Rehabilitation Service, Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304, USA.
authors.forename: Wen-Wu
authors.initials: WW
authors.lastname: Li
authors.forename: Tian-Zhi
authors.initials: TZ
authors.lastname: Guo
authors.forename: De-yong
authors.initials: DY
authors.lastname: Liang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Sun
authors.forename: Wade S
authors.initials: WS
authors.lastname: Kingery
authors.forename: J David
authors.initials: JD
authors.lastname: Clark
mesh_terms: D000818:Animals; D020918:Complex Regional Pain Syndromes / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism*; D064729:Neurokinin-1 Receptor Antagonists; D059225:Nociception / Q000502:physiology*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D013373:Substance P / Q000502:physiology*; D013978:Tibial Fractures / Q000378:metabolism*
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; D007211:Indoles; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D013373:Substance P