Overexpression of Nerve Growth Factor in Skin Selectively Affects the Survival and Functional Properties of Nociceptors

Abstract

Mice that overexpress nerve growth factor (NGF-OE) in the skin have double the normal number of cutaneous sensory neurons, have increased innervation of the skin and spinal cord, and are hyperalgesic. Here, we have asked whether the increased cutaneous NGF level results in a selective survival of only certain functional types of neurons and whether it changes the properties of cutaneous neurons. Using electron microscopy, we show that the number of both myelinated and unmyelinated nociceptors increases substantially in NGF-OE mice by a factor of 3.3 and 1.5, respectively. Using extracellular recordings from single units, we demonstrate that large myelinated (Abeta) fibers are unchanged in prevalence and receptive properties. In contrast, among thin myelinated (Adelta) fibers, the percentage of nociceptors increased from a normal 65 to 97%, consistent with a selective survival of nociceptors during embryogenesis. These afferents showed a twofold increase in their mechanical responsiveness, but their heat responsiveness remained normal. Among unmyelinated (C) fibers, there was a profound increase in the percentage of heat responsive neurons from a normal 42 to 96%. This change cannot be accounted for by a selective survival of heat-sensitive neurons. Unmyelinated nociceptors increased fourfold in their thermal responsiveness but decreased in mechanical responsiveness. Therefore, target-derived NGF selectively rescues nociceptors during the period of programmed cell death with different efficacy for thin myelinated or unmyelinated fibers. NGF also affects the response to noxious heat or mechanical stimuli in each group differently, implying specific regulations of transduction processes rather than general changes of excitability.