title: Roles of Gr-1+ leukocytes in postincisional nociceptive sensitization and inflammation.
abstract: BACKGROUND
  Neutrophils are one of the predominant immune cells initially migrating to surgical wound edges. They produce mediators both associated with supporting (interleukin [IL]-1β, C5a) and reducing (opioid peptides) pain. Studies demonstrate neutrophil depletion/blockade reduces nociceptive sensitization after nerve injury and carrageenan administration, but enhance sensitization in complete Freund's adjuvant inflammation. This research identifies the contribution of infiltrating neutrophils to incisional pain and inflammation.
  
  
  METHODS
  Antibody-mediated Gr1 neutrophil depletion preceded hind paw incisions. Sensitization to mechanical and thermal stimuli, effects on edema and local levels of IL-1β and C5a were measured. Local effects of C5a or IL-1 receptor antagonists PMX-53 and anakinra on sensitization after neutrophil depletion were examined. Groups of 4-8 mice were used.
  
  
  RESULTS
  Anti-Gr1 antibody depleted more than 90% of circulating and infiltrating skin neutrophils after incision. Neutrophil depletion did not change magnitude or duration of mechanical hypersensitivity in incised mice. However, paw edema was significantly reduced and heat hypersensitivity was slightly increased in depleted animals. In depleted animals IL-1β levels were half of controls 24 h after incision, whereas C5a levels were increased in both. Prominent IL-1β immunohistochemical staining of epidermis was seen in both groups. PMX-53 and anakinra reduced incisional mechanical and heat nociceptive sensitization to the same extent, regardless of neutrophil depletion.
  
  
  CONCLUSIONS
  Neutrophil-derived IL-1β and C5a do not appear to contribute critically to peri-incisional nociceptive signaling. Other sources of mediators, such as epidermal cells, may need to be considered. Controlling inflammatory activation of resident cells in epidermis/deeper structures may show therapeutic efficacy in reducing pain from surgical incisions.
authors: Anesthesiology Service, Veterans Administration Palo Alto Health Care System, Palo Alto, California, and Department of Anesthesia, Stanford University, Palo Alto, California, USA. psahbaie@stanford.edu
authors: Peyman
authors: P
authors: Sahbaie
authors: Xiangqi
authors: X
authors: Li
authors: Xiaoyou
authors: X
authors: Shi
authors: J David
authors: JD
authors: Clark
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000502:physiology; D015936:Complement C5a / Q000032:analysis; D007249:Inflammation / Q000209:etiology*; D053583:Interleukin-1beta / Q000032:analysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000502:physiology*; D010146:Pain / Q000503:physiopathology*; D019707:Receptors, Chemokine / Q000032:analysis / Q000502:physiology*
chemical_list: D000950:Antigens, Ly; C503133:Gr-1 protein, mouse; D053583:Interleukin-1beta; C480309:Ly6G antigen, mouse; D019707:Receptors, Chemokine; D015936:Complement C5a