On the role of nerve growth factor in the development of myelinated nociceptors

Abstract

We have previously demonstrated that administration of antisera against NGF (anti-NGF) can have profound effects on developing primary afferents (Ritter et al., 1991). Chronic administration of anti-NGF to rats beginning on the day of birth results in a severe depletion of cutaneous A delta high-threshold mechanoreceptors (HTMRs) from the sural nerve. Here we have carried out further experiments in order to define the period of time over which this change in the cutaneous afferent population can be produced, and to investigate a possible mechanism for the change. Treatment with anti-NGF from postnatal day (PND) 0–14 resulted in a depletion of cutaneous A delta HTMRs from the sural nerve and also a 20% loss of sensory neurons. However, treatment from PND 2–14 produced an identical deficit of HTMRs without any accompanying cell death. Thus, the depletion of cutaneous A delta HTMRs can be achieved in the absence of cell death induced by anti-NGF treatment. It was also found that a 7 d treatment from PND 4–11 was sufficient to reproduce this effect, but that 7 d treatments earlier (PND 2–9) or later (PND 7–14) within the first 2 weeks were much less effective. This critical period, PND 4–11, corresponds to a period of anatomical change in the innervation of the skin, from epidermal innervation to primarily dermal innervation (Fitzgerald, 1967; Reynolds et al., 1991). In every case where anti-NGF treatment reduced the proportion of HTMRs, there was a reciprocal increase in the proportion of sensitive A delta hair follicle (D-hair) afferents. We hypothesize that in the absence of NGF, developing cutaneous A delta HTMRs do not die but innervate novel targets in the dermis and become D-hair afferents instead.

The Low-Affinity Neurotrophin Receptor p75 Regulates the Function But Not the Selective Survival of Specific Subpopulations of Sensory Neurons

“…Because no specific marker for heat-sensitive AM fibers is available at this time, we cannot exclude the possibility that there may be selective cell death of heat-sensitive AM fibers. However, we favor the explanation that the heat-sensitive AM fibers in p75Ϫ/Ϫ mice underwent a phenotype switch, because other studies have shown that AM nociceptors undergo a permanent phenotype switch to D-hair receptors after postnatal treatment with antibodies that neutralizes endogenous NGF (Ritter et al, 1991;Lewin et al, 1992). Additional evidence from our laboratory suggests that the ligand responsible for the change in AM fibers in p75Ϫ/Ϫ mice is NGF, because NT-3, BDNF, or NT-4 are not required for the survival or function of AM nociceptors (Koltzenburg et al, 1995;Airaksinen et al, 1996;Stucky et al, 1996).…”

Derivation of Enriched Oligodendrocyte Cultures and Oligodendrocyte/Neuron Myelinating Co-cultures from Post-natal Murine Tissues

“…Other methods, such as derivation via neurospheres 7,8 , rely on the mitogenic properties of GFs such as basic fibroblast growth factor (bFGF), epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) for OPC expansion. Similarly, using postnatal (P5-10) mice for DRGNs avoids the requirement of supplementing the culture media with nerve growth factor (NGF), a neurotrophic factor required for the in vitro survival of embryonic DRGNs 9,10 . It is of interest to avoid using NGF as it negatively influences the myelinating capacity of OLs when cultured with DRGNs 4 .…”

A5-Positive Primary Sensory Neurons Are Nonpermissive for Productive Infection with Herpes Simplex Virus 1 In Vitro

“…This postnatal reduction in the percentage of TrkA ϩ neurons occurs gradually over 3 weeks (postnatal day 1 [P1] to P21), coinciding with the critical period during which alteration of neurotrophins can permanently alter the physiology of neonatal dorsal root and trigeminal ganglion neurons (19,25). Downregulation of TrkA by IB4-binding neurons results in differences in expression profiles and signaling cascades in response to certain classes of stimuli (33,39,53).…”