Comment on “Neutrophils: are they hyperalgesic or anti-hyperalgesic?”

We thank Cunha and Verri [1] for their constructive comments about our manuscript “Selective local PMN recruitment by CXCL1 or CXCL2/3 injection does not cause inflammatory pain” [2]. They raise several important issues concerning the role of polymorphonuclear cells (PMN), of chemokines, and of IL-1β in the induction of inflammatory hyperalgesia. Initially, the authors mention that their group has previously shown that certain chemokines and cytokines can induce hyperalgesia [3, 4], whereas in our study, chemokine (CXCL1, CXCL2/3) injection did not cause hyperalgesia. We agree with their comment that this discrepancy is most likely a result of different behavioral methods used. This issue is discussed in detail in our manuscript [2]. Cunha and Verri then show data that local PMN infiltration [measured indirectly by myeloperoxidase (MPO) activity] and mechanical hyperalgesia (measured by the von Frey test) are low in early inflammation [i.e., 2 h post-complete Freund’s adjuvant (CFA)] and increase in parallel within the first 6 h of CFA injection into the rat paw. Based on these correlative data they postulate that i) early time-points of inflammation are not ideal, and ii) PMN depletion at later time-points would be required to analyze the role of PMN in inflammatory hyperalgesia.