Summary Primary nociceptors relay painful touch information from the periphery to the spinal cord. While it is established that signals generated by the 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 receptor 1 (TNFR1) as a critical modifier of TrkA and Ret signaling in peptidergic and non-peptidergic nociceptors. In particular, TrkA+ peptidergic nociceptors require TNFα-TNFR1 forward signaling to suppress NGF-mediated neurite growth, survival, excitability, and differentiation. Conversely, TNFR1-TNFα reverse signaling augments the neurite growth and excitability of Ret+ non-peptidergic 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 non-peptidergic nociceptors, respectively.
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