title: Morphine reduces local cytokine expression and neutrophil infiltration after incision.
abstract: BACKGROUND
  Inflammation and nociceptive sensitization are hallmarks of tissue surrounding surgical incisions. Recent studies demonstrate that several cytokines may participate in the enhancement of nociception near these wounds. Since opioids like morphine interact with neutrophils and other immunocytes, it is possible that morphine exerts some of its antinociceptive action after surgical incision by altering the vigor of the inflammatory response. On the other hand, keratinocytes also express opioid receptors and have the capacity to produce cytokines after injury. Our studies were directed towards determining if opioids alter cytokine production near incisions and to identify cell populations responsible for producing these cytokines.
  
  
  RESULTS
  A murine incisional model was used to measure the effects of acute morphine administration (0.1-10 mg/kg) on nociceptive thresholds, neutrophil infiltration and cytokine production in hind paw skin 30 minutes and 2 hours after incision. Incised hind paws displayed profound allodynia which was reduced by morphine (0.1-10 mg/kg) in the 2 hours following incision. Skin samples harvested from these mice showed enhanced levels of 5 cytokines: IL-1 beta, IL-6, tumor necrosis factor alpha (TNFalpha), granulocyte colony stimulating factor (G-CSF) and keratinocyte-derived cytokine (KC). Morphine reduced these incision-stimulated levels. Separate analyses measuring myeloperoxidase (MPO) and using immunohistochemistry demonstrated that morphine dose-dependently reduced the infiltration of neutrophils into the peri-incisional tissue. The dose of morphine required for reduction of cytokine accumulation, however, was below that required for inhibition of peri-incisional neutrophil infiltration. Additional immunohistochemical studies revealed wound edge keratinocytes as being an important source of cytokines in the acute phase after incision.
  
  
  CONCLUSIONS
  Acute morphine administration of doses as low as 0.1 mg/kg reduces peri-incisional cytokine expression. A reduction in neutrophil infiltration does not provide a complete explanation for this effect, and keratinocytes may be responsible for some incision area cytokine production. These studies suggest that morphine may alter the inflammatory milieu of incisional wounds, but these alterations do not likely contribute significantly to analgesia in the acute setting.
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, Stanford, CA, USA. djclark@stanford.edu
authors.forename: J David
authors.initials: JD
authors.lastname: Clark
authors.forename: Xiaoyou
authors.initials: X
authors.lastname: Shi
authors.forename: Xiangqi
authors.initials: X
authors.lastname: Li
authors.forename: Yanli
authors.initials: Y
authors.lastname: Qiao
authors.forename: DeYong
authors.initials: D
authors.lastname: Liang
authors.forename: Martin S
authors.initials: MS
authors.lastname: Angst
authors.forename: David C
authors.initials: DC
authors.lastname: Yeomans
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D004817:Epidermis / Q000276:immunology / Q000293:injuries / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D006614:Hindlimb; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D010149:Postoperative Pain / Q000188:drug therapy* / Q000276:immunology; D009195:Peroxidase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014945:Wound Healing / Q000276:immunology
chemical_list: D000701:Analgesics, Opioid; D018925:Chemokines; D016207:Cytokines; D053583:Interleukin-1beta; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D016179:Granulocyte Colony-Stimulating Factor; C074302:keratinocyte-derived chemokines; D009020:Morphine; D009195:Peroxidase