Endothelial cells play an essential role in the thermal hyperalgesia induced by nerve growth factor

Abstract

Nerve growth factor (NGF) is a potent mediator of inflammatory hyperalgesia, in addition to roles in the development and maintenance of neurons. We provide evidence for the novel concept that microvascular endothelial cells play a critical primary role in NGF-mediated events that lead to inflammatory hyperalgesia in rat skin. We show that, surprisingly, neutrophils are not directly activated by NGF, although local administration of NGF mediates thermal hyperalgesia via mechanisms involving concomitant neutrophil accumulation. The co-administration of actinomycin D with NGF negated both neutrophil accumulation and thermal hyperalgesia, indicating the dependence of NGF on local de novo protein synthesis. More significantly, an antibody against the endothelial-derived adhesion molecule ICAM-1 also blocked neutrophil accumulation and thermal hyperalgesia. Finally the ability of NGF to stimulate ICAM-1 in human cultured umbilical vein endothelial cells is shown. We propose that NGF acts primarily to activate endothelial cells and that this response is essential for the ensuing neutrophil accumulation and hyperalgesia. The findings reveal a central role of the endothelial cell in initiating NGF-dependent inflammatory hyperalgesia and emphasize the importance of further investigations aimed at examining the feasibility of new therapeutic strategies that target NGF.

Neutrophils: are they hyperalgesic or anti-hyperalgesic?

“…In addition, in the CFA hyperalgesia inflammatory model, a sequential release of IL-1␤, 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.…”

Involvement of transient receptor potential vanilloid 1 in the vascular and hyperalgesic components of joint inflammation

“…Hind paw thermal nociceptive thresholds were determined before and at the stated times after administration of test agents, according to the Hargreaves method (21) adapted for mice (22). Briefly, the mice were housed in a behavior box on a glass platform and allowed to acclimatize for 30 minutes before readings.…”

Antagonism of Nerve Growth Factor-TrkA Signaling and the Relief of Pain

“…These rapid effects in the rat are thought to be mediated primarily through NGF binding with TrkA expressed on mast cells, causing degranulation and release of a variety of algogenic mediators, such as histamine, prostaglandin E2, serotonin, hydrogen ions, and bradykinin, as well as additional NGF (fig 1b), although the contribution of mast cells is not as clear in humans. NGF can also be produced by non-inflammatory cells, such as keratinocytes 65 and endothelial cells, 66 in addition to other inflammatory cells, such as fibroblasts 67 and T cells in various in vitro culture models. 68 …”