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Originally published online as doi:10.1189/jlb.0406244 on August 7, 2006

Published online before print August 7, 2006
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(Journal of Leukocyte Biology. 2006;80:727-728.)
© 2006 by Society for Leukocyte Biology

Neutrophils: are they hyperalgesic or anti-hyperalgesic?

T. M. Cunha1 and W. A. Verri, Jr

Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil

1 Correspondence: Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Avenida Bandeirantes, 3900, 14049-900-Ribeirão Preto, São Paulo, Brazil. E-mail: thicunha{at}usp.br

Key Words: inflammation • chemokines • IL-1

CXC chemokines present an important role in the development of inflammation by triggering a coordinated neutrophil migration to the inflammatory focus. Neutrophils are the main effector cell type in the inflammatory reaction responsible for antigen destruction. However, in some conditions, those are the main cells responsible for the inflammatory lesions. In a recent paper, Rittner et al. [1 ] demonstrated that although the administration [intraplantar (i.pl.)] of different CXC chemokines induces activation and migration of polymorphonuclear cells (PMN) to the rat paws, no reduction in mechanical or thermal nociceptive threshold is detected. Moreover, in the same study, it was shown that the elimination of PMN in the inflammatory site by the systemic treatment with anti-PMN antibody did not alter inflammatory hyperalgesia induced by complete Freund’s adjuvant (CFA) [1 ]. In addition to the lack of neutrophil participation in CFA hyperalgesia, there is also evidence that PMN may inhibit this phenomenon by producing opioids in the inflammatory site [2 ].

Concerning the hyperalgesic effect of CXC chemokines, it has been demonstrated that these cytokines are responsible for the stimulation of a sympathetic component of inflammatory hyperalgesia [3 , 4 ]. These discrepant data might be a consequence of the methodological approach used by each study. However, the absence of neutrophil participation in CFA-induced hyperalgesia should be analyzed in more detail. It is noteworthy that the hyperalgesia was evaluated 2 h after CFA i.pl. injection. This is certainly not the ideal time to evaluate the participation of neutrophil in CFA-induced hyperalgesia. Although 2 h after CFA injection, hyperalgesia is already significant (Fig. 1A ), a consistent neutrophil migration to the CFA-injected paw is reached in later time-points (Fig. 1B) . Corroborating with this fact, CXC chemokines, which seem important to neutrophil migration in this model, reach a maximal release in time-points later than 2 h [2 ]. Therefore, it is possible that the time evaluated was crucial for the negative results concerning the correlation between PMN migration and hyperalgesia obtained by Rittner et al. [1 ] Maybe, investigating the impact of neutrophil elimination on CFA-induced hyperalgesia in the function of the time would be helpful to elucidate their role in inflammatory hyperalgesia.


Figure 1
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  		Figure 1. CFA induces time-dependent mechanical hyperalgesia and neutrophil migration to the rat paw. (A) i.pl. injection of CFA (150 µL/paw) induces mechanical hyperalgesia evaluated by the electronic version of von Frey methods (Ugo Basile). Hyperalgesia was evaluated before, 2, 4, and 6 h after CFA injection. (B) Neutrophil migration to the CFA (150 µL/paw)-injected paw was evaluated indirectly by the measurement of myeloperoxidase activity in the rat paw. *, Statistically significant difference compared with the saline (150 µL/paw) paw-injected group (P<0.05).

Another intriguing issue is that Rittner et al. [1 ] showed that although the inhibition of CFA-induced neutrophil migration to the inflamed paw did not reduce hyperalgesia, it did inhibit the IL-1ß release in the skin paw. Furthermore, it was observed that although CXC chemokines do not produce hyperalgesia, they induce significant IL-1ß release in the rat paw skin. In contrast, the participation of IL-1ß on the genesis of inflammatory hyperalgesia has been demonstrated extensively. In fact, IL-1ß was the first cytokine demonstrated to be hyperalgesic, and treatment with antibody against IL-1ß or IL-1 receptor antagonist inhibits CFA- and carrageenan-induced mechanical and thermal hyperalgesia in rats [5 , 6 ]. In addition, in the CFA hyperalgesia inflammatory model, a sequential release of IL-1ß, triggering nerve growth factor (NGF) production, has been demonstrated [5 ]. Besides NGF-direct action on nociceptors promoting hyperalgesia, it also induces indirect hyperalgesia, at least in part, dependent on leukotriene production, which in turn, induces neutrophil migration [7 8 9 10 11 ]. This last information together with the present data (Fig. 1A and 1B) suggest that neutrophils might be important to CFA-induced hyperalgesia.

Supporting this hypothesis, neutrophils seem important to hyperalgesia in a model of joint inflammation [12 ]. Indeed, the inhibition of the synthesis of the neutrophil chemoattractant leukotriene B4 (LTB4) was effective in diminishing articular hyperalgesia and neutrophil influx to the joint. Corroborating, the hyperalgesic activity of LTB4 is inhibited in rats depleted of their neutrophils, and the neutrophil migration kinetics correlates with the hyperalgesic effect of LTB4 in humans [13 , 14 ].

Concluding, there are discrepant results in the literature concerning the role of neutrophils in the hyperalgesia induction. Actually, the role of neutrophils in the genesis of hyperalgesia may depend on the type and intensity of stimuli and mainly on the different stages of the inflammation. Therefore, further studies are necessary to ascertain the relative contribution of neutrophils to the genesis or to the control of this important inflammatory event.

Received April 4, 2006; revised April 27, 2006; accepted May 16, 2006.

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