Crucial role of neutrophils in the development of mechanical inflammatory hypernociception

Abstract

Neutrophil migration is responsible for tissue damage observed in inflammatory diseases. Neutrophils are also implicated in inflammatory nociception, but mechanisms of their participation have not been elucidated. In the present study, we addressed these mechanisms in the carrageenan-induced mechanical hypernociception, which was determined using a modification of the Randall-Sellito test in rats. Neutrophil accumulation into the plantar tissue was determined by the contents of myeloperoxidase activity, whereas cytokines and PGE(2) levels were measured by ELISA and radioimmunoassay, respectively. The pretreatment of rats with fucoidin (a leukocyte adhesion inhibitor) inhibited carrageenan-induced hypernociception in a dose- and time-dependent manner. Inhibition of hypernociception by fucoidin was associated with prevention of neutrophil recruitment, as it did not inhibit the hypernociception induced by the direct-acting hypernociceptive mediators, PGE(2) and dopamine, which cause hypernociception, independent of neutrophils. Fucoidin had no effect on carrageenan-induced TNF-alpha, IL-1beta, and cytokine-induced neutrophil chemoattractant 1 (CINC-1)/CXCL1 production, suggesting that neutrophils were not the source of hypernociceptive cytokines. Conversely, hypernociception and neutrophil migration induced by TNF-alpha, IL-1beta, and CINC-1/CXCL1 was inhibited by fucoidin, suggesting that neutrophils are involved in the production of direct-acting hypernociceptive mediators. Indeed, neutrophils stimulated in vitro with IL-1beta produced PGE(2), and IL-1beta-induced PGE(2) production in the rat paw was inhibited by the pretreatment with fucoidin. In conclusion, during the inflammatory process, the migrating neutrophils participate in the cascade of events leading to mechanical hypernociception, at least by mediating the release of direct-acting hypernociceptive mediators, such as PGE(2). Therefore, the blockade of neutrophil migration could be a target to development of new analgesic drugs.

NLRP3 inflammasome–mediated neutrophil recruitment and hypernociception depend on leukotriene B4 in a murine model of gout

“…Previous studies have shown that neutrophils may be the main effectors of inflammatory pain in different models of inflammation (20,31,37). In our study, prevention of neutrophil influx decreased joint hypernociception, demonstrating a major contribution of these cells in driving joint dysfunction after MSU crystal injection.…”

The chemokine Bv8/prokineticin 2 is up-regulated in inflammatory granulocytes and modulates inflammatory pain

“…Inflammatory stimuli activate the release of the cytokine G-CSF that stimulates the synthesis and release of the chemokine PK2 by neutrophils, and this chemokine, in turn, stimulates macrophage chemotaxis and cytokine release by recruited macrophages. Although other leukocyte-derived chemokines are known to produce hypernociception in rats and mice (2,29,30) their pronociceptive activity and potency in activating G protein-coupled receptors is Ϸ100-500 times lower than that of PK2, and their receptors are far less abundant than PKRs in the primary sensory neurons under basal conditions (15,16,31,32).…”

“…hypernociception ͉ inflammation ͉ prokineticin receptors I n past years, several groups have generated convincing evidence that neutrophil-associated hyperalgesia results from the neutrophil release of proinflammatory pronociceptive factors, including products of arachidonic acid metabolism (1,2) and cytokines such as IL-1␤, IL-8, IL-12, TNF-␣, and macrophage inflammatory proteins MIP-1a and MIP-1b (3,4). Belonging to the chemokine family, the recently discovered prokineticins [Bv8, MIT, prokineticin 1 (PK1), and prokineticin 2 (PK2)] (5-9) activate two G protein-linked PK receptors (PKR1 and PKR2) (10)(11)(12) localized in the brain, dorsal root ganglia (DRG) neurons, granulocytes, macrophages, and endothelial cells.…”

Fractalkine mediates inflammatory pain through activation of satellite glial cells

“…The supernatants of isolated, cultured SGCs were collected 6 h after incubation with fractalkine (1-100 ng/mL) or medium (control) treatment. The supernatants were used to determine the levels of TNF-α and IL-1β by ELISA, as described previously (45).…”