TNF-α/TNFR1 signaling is required for the development and function of primary nociceptors.

Abstract:

:Primary nociceptors relay painful touch information from the periphery to the spinal cord. Although it is established that signals generated by receptor tyrosine kinases TrkA and Ret coordinate the development of distinct nociceptive circuits, mechanisms modulating TrkA or Ret pathways in developing nociceptors are unknown. We have identified tumor necrosis factor (TNF) receptor 1 (TNFR1) as a critical modifier of TrkA and Ret signaling in peptidergic and nonpeptidergic nociceptors. Specifically, TrkA+ peptidergic nociceptors require TNF-α-TNFR1 forward signaling to suppress nerve growth factor (NGF)-mediated neurite growth, survival, excitability, and differentiation. Conversely, TNFR1-TNF-α reverse signaling augments the neurite growth and excitability of Ret+ nonpeptidergic nociceptors. The developmental and functional nociceptive defects associated with loss of TNFR1 signaling manifest behaviorally as lower pain thresholds caused by increased sensitivity to NGF. Thus, TNFR1 exerts a dual role in nociceptor information processing by suppressing TrkA and enhancing Ret signaling in peptidergic and nonpeptidergic nociceptors, respectively.

journal_name

Neuron

journal_title

Neuron

authors

Wheeler MA,Heffner DL,Kim S,Espy SM,Spano AJ,Cleland CL,Deppmann CD

doi

10.1016/j.neuron.2014.04.009

subject

Has Abstract

pub_date

2014-05-07 00:00:00

pages

587-602

issue

3

eissn

0896-6273

issn

1097-4199

pii

S0896-6273(14)00299-2

journal_volume

82

pub_type

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