title: Selective local PMN recruitment by CXCL1 or CXCL2/3 injection does not cause inflammatory pain.
abstract: Polymorphonuclear cells (PMN) are recruited in early inflammation and are believed to contribute to inflammatory pain. However, studies demonstrating a hyperalgesic role of PMN did not examine selective PMN recruitment or did not document effective PMN recruitment. We hypothesized that hyperalgesia does not develop after chemokine-induced PMN selective recruitment and is independent of PMN infiltration in complete Freund's adjuvant (CFA)-induced, local inflammation. PMN were recruited by intraplantar injection of CXC chemokine ligand 1 (CXCL1; keratinocyte-derived chemokine), CXCL2/3 (macrophage inflammatory protein-2), or CFA, with or without preceding systemic PMN depletion. Chemokine inoculation resulted in dose (0-30 microg)- and time (0-12 h)-dependent, selective recruitment of PMN as quantified by flow cytometry. CXCL2/3, but not CXCL1, was less effective at high doses, probably as a result of significant down-regulation of CXC chemokine receptor 2 expression on blood PMN. Neither chemokine caused mechanical or thermal hyperalgesia as determined by the Randall-Selitto and Hargreaves test, respectively, despite comparable expression of activation markers (i.e., CD11b, CD18, and L-selectin) on infiltrating PMN. In contrast, CFA injection induced hyperalgesia, independent of PMN recruitment. c-Fos mRNA and immunoreactivity in the spinal cord were increased significantly after inoculation of CFA-independent of PMN-migration but not of CXCL2/3. Measurement of potential hyperalgesic mediators showed that hyperalgesia correlated with local prostaglandin E2 (PGE2) but not with interleukin-1beta production. In summary, hyperalgesia, local PGE2 production, and spinal c-Fos expression occur after CFA-induced inflammation but not after CXCL1- or CXCL2/3-induced, selective PMN recruitment. Thus, PMN seem to be less important in inflammatory hyperalgesia than previously thought.
authors.affiliation: Klinik für Anaesthesiologie und operative Intensivmedizin, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Germany.
authors.forename: Heike L
authors.initials: HL
authors.lastname: Rittner
authors.forename: Shaaban A
authors.initials: SA
authors.lastname: Mousa
authors.forename: Dominika
authors.initials: D
authors.lastname: Labuz
authors.forename: Karin
authors.initials: K
authors.lastname: Beschmann
authors.forename: Michael
authors.initials: M
authors.lastname: Schäfer
authors.forename: Christoph
authors.initials: C
authors.lastname: Stein
authors.forename: Alexander
authors.initials: A
authors.lastname: Brack
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000276:immunology; D015415:Biomarkers / Q000378:metabolism; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D019743:Chemokines, CXC / Q000276:immunology* / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D005620:Freund's Adjuvant / Q000494:pharmacology; D006930:Hyperalgesia / Q000139:chemically induced / Q000276:immunology / Q000503:physiopathology; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology* / Q000503:physiopathology; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology*; D010146:Pain / Q000139:chemically induced / Q000276:immunology* / Q000503:physiopathology; D010147:Pain Measurement; D020671:Posterior Horn Cells / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
chemical_list: D000954:Antigens, Surface; D015415:Biomarkers; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D019743:Chemokines, CXC; C513297:Cxcl1 protein, rat; C513296:Cxcl2 protein, rat; D016207:Cytokines; D016760:Proto-Oncogene Proteins c-fos; D005620:Freund's Adjuvant; D015232:Dinoprostone