Neutralization of endogenous NGF prevents the sensitization of nociceptors supplying inflamed skin.

Abstract

Evidence suggests that nerve growth factor (NGF) is an important mediator in inflammatory pain states: NGF levels increase in inflamed tissue, and neutralization of endogenous NGF prevents the hyperalgesia which normally develops during inflammation of the skin. Here we asked whether NGF contributes to sensitization of primary afferent nociceptors, which are an important component of pain and hyperalgesia in inflamed tissue. An in vitro skin nerve preparation of the rat was used to directly record the receptive properties of thin myelinated (Adelta) and unmyelinated (C) nociceptors innervating normal hairy skin, carrageenan-inflamed skin and carrageenan-inflamed skin where endogenous NGF had been neutralized by application of a trkA-IgG (tyrosine kinase Aimmunoglobulin G) fusion molecule. Following carrageenan inflammation, there was a marked increase in the proportion of nociceptors which displayed ongoing activity (50% of nociceptors developed spontaneous activity compared to 4% of nociceptors innervating normal uninflamed skin), and this was reflected in a significant increase in the average ongoing discharge activity. Spontaneously active fibres were sensitized to heat and displayed a more than twofold increase in their discharge to a standard noxious heat stimulus. Furthermore, the number of nociceptors responding to the algesic mediator bradykinin increased significantly from 28% to 58%. By contrast, the mechanical threshold of nociceptive afferents did not change during inflammation. When the NGF-neutralizing molecule trkA-IgG was coadministered with carrageenan at the onset of the inflammation, primary afferent nociceptors did not sensitize and displayed essentially normal response properties, although the inflammation as evidenced by tissue oedema developed normally. We therefore conclude that NGF is a crucial component for the sensitization of primary afferent nociceptors associated with tissue inflammation.