title: The connection of monocytes and reactive oxygen species in pain.
abstract: The interplay of specific leukocyte subpopulations, resident cells and proalgesic mediators results in pain in inflammation. Proalgesic mediators like reactive oxygen species (ROS) and downstream products elicit pain by stimulation of transient receptor potential (TRP) channels. The contribution of leukocyte subpopulations however is less clear. Local injection of neutrophilic chemokines elicits neutrophil recruitment but no hyperalgesia in rats. In meta-analyses the monocytic chemoattractant, CCL2 (monocyte chemoattractant protein-1; MCP-1), was identified as an important factor in the pathophysiology of human and animal pain. In this study, intraplantar injection of CCL2 elicited thermal and mechanical pain in Wistar but not in Dark Agouti (DA) rats, which lack p47(phox), a part of the NADPH oxidase complex. Inflammatory hyperalgesia after complete Freund's adjuvant (CFA) as well as capsaicin-induced hyperalgesia and capsaicin-induced current flow in dorsal root ganglion neurons in DA were comparable to Wistar rats. Macrophages from DA expressed lower levels of CCR2 and thereby migrated less towards CCL2 and formed limited amounts of ROS in vitro and 4-hydroxynonenal (4-HNE) in the tissue in response to CCL2 compared to Wistar rats. Local adoptive transfer of peritoneal macrophages from Wistar but not from DA rats reconstituted CCL2-triggered hyperalgesia in leukocyte-depleted DA and Wistar rats. A pharmacological stimulator of ROS production (phytol) restored CCL2-induced hyperalgesia in vivo in DA rats. In Wistar rats, CCL2-induced hyperalgesia was completely blocked by superoxide dismutase (SOD), catalase or tempol. Likewise, inhibition of NADPH oxidase by apocynin reduced CCL2-elicited hyperalgesia but not CFA-induced inflammatory hyperalgesia. In summary, we provide a link between CCL2, CCR2 expression on macrophages, NADPH oxidase, ROS and the development CCL2-triggered hyperalgesia, which is different from CFA-induced hyperalgesia. The study further supports the impact of CCL2 and ROS as potential targets in pain therapy.
authors: Klinik und Poliklinik für Anaesthesiologie, Universitätsklinikum, Würzburg, Germany.
authors: Dagmar
authors: D
authors: Hackel
authors: Diana
authors: D
authors: Pflücke
authors: Annick
authors: A
authors: Neumann
authors: Johannes
authors: J
authors: Viebahn
authors: Shaaban
authors: S
authors: Mousa
authors: Erhard
authors: E
authors: Wischmeyer
authors: Norbert
authors: N
authors: Roewer
authors: Alexander
authors: A
authors: Brack
authors: Heike Lydia
authors: HL
authors: Rittner
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D016166:Free Radical Scavengers / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006930:Hyperalgesia / Q000139:chemically induced; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D008297:Male; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D010146:Pain / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000378:metabolism
chemical_list: D018932:Chemokine CCL2; D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D019255:NADPH Oxidases
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