Overexpression of nerve growth factor in skin selectively affects the survival and functional properties of nociceptors

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 whet her the increased cutaneous NGF level results in a selective survival of on ly certain functional types of neurons and whether it changes the propertie s 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 r ecordings from single units, we demonstrate that large myelinated (A beta) fibers are unchanged in prevalence and receptive properties. In contrast, a mong thin myelinated (A delta) fibers, the percentage of nociceptors increa sed from a normal 65 to 97%, consistent with a selective survival of nocice ptors during embryogenesis. These afferents showed a twofold increase in th eir mechanical responsiveness, but their heat responsiveness remained norma l. Among unmyelinated (C) fibers, there was a profound increase in the perc entage of heat responsive neurons from a normal 42 to 96%. This change cann ot be accounted for by a selective survival of heat-sensitive neurons. Unmy elinated nociceptors increased fourfold in their thermal responsiveness but decreased in mechanical responsiveness. Therefore, target-derived NGF sele ctively rescues nociceptors during the period of programmed cell death with different efficacy for thin myelinated or unmyelinated fibers. NGF also af fects the response to noxious heat or mechanical stimuli in each group diff erently, implying specific regulations of transduction processes rather tha n general changes of excitability.