Selective local PMN recruitment by CXCL1 or CXCL2/3 injection does not cause inflammatory pain

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 μg)‐ 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 E 2 (PGE 2 ) but not with interleukin‐1β production. In summary, hyperalgesia, local PGE 2 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.