title: Tissue monocytes/macrophages in inflammation: hyperalgesia versus opioid-mediated peripheral antinociception.
abstract: BACKGROUND
  Opioid-containing leukocytes migrate to peripheral sites of inflammation. On exposure to stress, opioid peptides are released, bind to opioid receptors on peripheral sensory neurons, and induce endogenous antinociception. In later stages of Freund's complete adjuvant-induced local inflammation, monocytes/macrophages are a major opioid-containing leukocyte subpopulation, but these cells also produce proalgesic cytokines. In this study, the role of tissue monocytes/macrophages in hyperalgesia and in peripheral opioid-mediated antinociception was investigated.
  
  
  METHODS
  After intraplantar injection of Freund's adjuvant, leukocyte subpopulations and opioid-containing leukocytes were analyzed by flow cytometry in the inflamed paw in the presence or absence of monocyte/macrophage depletion by intraplantar injection of clodronate-containing liposomes (phosphate-buffered saline and empty liposomes served as controls). Paw volume was measured with a plethysmometer. Hyperalgesia was determined by measuring heat-induced paw withdrawal latency and paw pressure threshold. Paw pressure threshold was also measured after swim stress and injection of fentanyl.
  
  
  RESULTS
  At 48 and 96 h of inflammation, it was found that (1). monocytes/macrophages were the largest leukocyte subpopulation (> 55% of all leukocytes) and the predominant producers of opioid peptides (71-77% of all opioid-containing leukocytes in the paw), (2). clodronate-containing liposomes depleted monocytes/macrophages by 30-35% (P < 0.05), (3). hyperalgesia was unaltered by liposome injection (P > 0.05), and (4) opioid-containing leukocytes and swim stress but not fentanyl-induced antinociception were significantly decreased by clodronate-containing liposomes (P < 0.05, P > 0.05, all by t test; opioid-containing cells and swim stress-induced increase of paw pressure threshold were reduced by 35-42% and 20%, respectively).
  
  
  CONCLUSIONS
  Partial depletion of tissue monocytes/macrophages impairs peripheral endogenous opioid-mediated antinociception without affecting hyperalgesia.
authors.affiliation: Klinik für Anaesthesiologie und operative Intensivmedizin, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany. alexander.brack@charite.de
authors.forename: Alexander
authors.initials: A
authors.lastname: Brack
authors.forename: Dominika
authors.initials: D
authors.lastname: Labuz
authors.forename: Anu
authors.initials: A
authors.lastname: Schiltz
authors.forename: Heike L
authors.initials: HL
authors.lastname: Rittner
authors.forename: Halina
authors.initials: H
authors.lastname: Machelska
authors.forename: Michael
authors.initials: M
authors.lastname: Schäfer
authors.forename: Regina
authors.initials: R
authors.lastname: Reszka
authors.forename: Christoph
authors.initials: C
authors.lastname: Stein
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000493:pharmacokinetics / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D004002:Clodronic Acid / Q000493:pharmacokinetics / Q000494:pharmacology; D005283:Fentanyl / Q000008:administration & dosage / Q000494:pharmacology*; D005434:Flow Cytometry; D005528:Foot / Q000473:pathology; D005620:Freund's Adjuvant; D006358:Hot Temperature; D006930:Hyperalgesia / Q000139:chemically induced* / Q000473:pathology / Q000523:psychology; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology*; D007267:Injections; D008081:Liposomes; D008264:Macrophages / Q000473:pathology*; D008297:Male; D009000:Monocytes / Q000473:pathology*; D010147:Pain Measurement / Q000187:drug effects; D011312:Pressure; D051381:Rats; D017208:Rats, Wistar
chemical_list: D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D008081:Liposomes; D004002:Clodronic Acid; D005620:Freund's Adjuvant; D005283:Fentanyl