NGF-mediated sensitization of the excitability of rat sensory neurons is prevented by a blocking antibody to the p75 neurotrophin receptor

doi:10.1016/j.neulet.2004.05.042

Neuroscience Letters

Volume 366, Issue 2, 12 August 2004, Pages 187-192

https://doi.org/10.1016/j.neulet.2004.05.042 Get rights and content

Abstract

Nerve growth factor (NGF) can play a causal role in the initiation of hyperalgesia. Recent work demonstrates that NGF can act directly on nociceptive sensory neurons to augment their sensitivity to a variety of stimuli. Based on the existing literature, it is not clear whether this sensitization is mediated by the high-affinity TrkA receptor or the low-affinity p75 neurotrophin receptor. We examined whether a blocking antibody to the p75 neurotrophin receptor can prevent the NGF-induced enhancement of excitability in capsaicin-sensitive small-diameter sensory neurons that have been isolated from the adult rat. In this report, pretreatment with the p75 blocking antibody completely prevents the NGF-induced increase in the number of action potentials evoked by a ramp of depolarizing current as well as the suppression of a delayed rectifier-type of potassium current(s) in these neurons. Although the sensitization by NGF was blocked, the antibody had no effect on the capacity of ceramide, a putative downstream signaling molecule, to either enhance the excitability or inhibit the potassium current. These results indicate that NGF can increase the excitability of nociceptive sensory neurons through activation of the p75 neurotrophin receptor and its consequent liberation of ceramide from neuronal sphingomyelins.

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Acknowledgements

This work was supported by NIH NS046084. We are grateful to Dr. Louis Reichardt (UCSF) for supplying the p75 blocking antibody and to Dr. Ted Cummins for his comments.

References (25)

X Jiang et al.
Prostaglandin E₂ inhibits the potassium current in sensory neurons from hyperalgesic Kv1.1 knockout mice
Neuroscience
(2003)
H Kase et al.
K-252 compounds, novel and potent inhibitors of protein kinase C and cyclic nucleotide-dependent kinases
Biochem. Biophys. Res. Commun.
(1987)
S.P Lad et al.
Individual and combined effects of TrkA and p75NTR nerve growth factor receptors. A role for the high affinity receptor site
J. Biol. Chem.
(2003)
B Liu et al.
Glutathione regulation of natural sphingomyelinase in tumor necrosis factor-α-induced cell death
J. Biol. Chem.
(1998)
B Liu et al.
Inhibition of the neutral magnesium-dependent sphingomyelinase by glutathione
J. Biol. Chem.
(1997)
I.J MacPhee et al.
Brain-derived neurotrophic factor binding to the p75 neurotrophin receptor reduces TrkA signaling while increasing serine phosphorylation in the TrkA intracellular domain
J. Biol. Chem.
(1997)
X.-Q Shu et al.
Nerve growth factor acutely sensitizes the response of adult rat sensory neurons to capsaicin
Neurosci. Lett.
(1999)
A Sutter et al.
Nerve growth factor receptors. Characterization of two distinct classes of binding sites in chick embryo sensory ganglia cells
J. Biol. Chem.
(1979)
J.M Verdi et al.
p75LNGFR regulates Trk signal transduction and NGF-induced neuronal differentiation in MAH cells
Neuron
(1994)
J Vesa et al.
p75 reduces TrkB tyrosine autophosphorylation in response to brain-derived neurotrophic factor and neurotrophin 4/5
J. Biol. Chem.
(2000)

G Weskamp et al.

Evidence that biological activity of NGF is mediated through a novel class of high affinity receptors

Neuron

(1991)

C.J Woolf et al.

Nerve growth factor contributes to the generation of inflammatory sensory hypersensitivity

Neuroscience

(1994)

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NGF-mediated sensitization of the excitability of rat sensory neurons is prevented by a blocking antibody to the p75 neurotrophin receptor

Abstract

Section snippets

Acknowledgements

Neuroscience

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Neurosci. Lett.

J. Biol. Chem.

Neuron

J. Biol. Chem.

Neuron

Neuroscience