Dual Action Pain Modulator

Sci. Signal.  20 May 2014:
Vol. 7, Issue 326, pp. ec131
DOI: 10.1126/scisignal.2005497

Specific classes of nociceptive neurons respond to different types of painful stimuli, such as pain-inducing chemicals released by damaged tissue, heat, cold, or pressure. Initially, development of the precursors of both peptidergic and nonpeptidergic nociceptive neurons requires nerve growth factor (NGF), which stimulates its receptor TrkA. Later, proper target innervation of peptidergic nociceptive neurons relies on NGF-TrkA, whereas that of nonpeptidergic nociceptive neurons relies on glial-derived neurotrophic factor (GNDF) family member neurturin and the receptor Ret. Wheeler et al. examined the mRNA abundance of all 23 members of the tumor necrosis factor (TNF) receptor (TNFR) family in embryonic dorsal root ganglion (DRG). They detected high abundance of the transcripts for TNFR1 and for p75NTR, an inhibitor of NGF-TrkA signaling. Immunohistochemistry confirmed that TNFR1 colocalized with markers of both peptidergic and nonpeptidergic nociceptive neurons and indicated the presence of TNF-α, the TNFR1 ligand, on sensory neurons in the DRG, the epidermis, and the spinal cord. Mice genetically deficient in TNF-α or TNFR1 (Tnf–/– or Tnfr1–/–) had increased density of nociceptive fibers in the skin and were hypersensitive to thermal and mechanical stimuli, indicating a reduced threshold for pain perception. Unexpectedly, there were relatively fewer Trk-positive nociceptive neurons at P0 in the mutant mice, but more at P14 and P30, suggesting that differentiation of the nociceptive neurons was altered. Indeed, mutant mice had a larger proportion of doubly positive Ret and TrkA precursor nociceptive neurons in the DRGs at P0, but at P14 and P30, only the proportion of nonpeptidergic nociceptive neurons was increased. However, compared with wild-type mice, the Tnf–/– or Tnfr1–/– mice had more projections from peptidergic neurons and fewer nonpeptidergic neuronal projections in the spinal cord. Furthermore, dissociated sensory neurons or DRG explants from wild-type mice exhibited faster NGF-mediated neurite outgrowth in the absence of exogenously added TNF-α compared with growth in the presence of TNF-α. DRG explants from the Tnf–/– or Tnfr1–/– mice exhibited increased outgrowth in response to NGF, suggesting that TNFR1 signaling inhibits NGF-mediated neurite outgrowth. In contrast, DRG explants from Tnf–/– or Tnfr1–/– mice exhibited decreased neurite outgrowth in response to neurturin, suggesting a positive role for TNF-α-TNFR1 signaling. Neurturin-stimulated outgrowth of neurites from DRG explants from Tnfr1–/– mice was rescued by the addition of soluble TNFR1, whereas the addition of TNF-α failed to rescue outgrowth from explants from Tnf–/– mice, suggesting that “reverse” signaling from TNFR1 to TNF-α and not “forward” signaling by TNF-α to TNFR1 mediated this enhancement of neurite outgrowth. Calcium-imaging studies showed that compared with those from wild-type mice, peptidergic nociceptive neurons isolated from the Tnf–/– or Tnfr1–/– mice were more excitable in response to ligands that activate pain-associated TRP channels and that the nonpeptidergic nociceptive neurons were less responsive to either ATP or TRP ligands in the mutant mice. Thus, TNF-α-TNFR1 signaling has opposite roles in suppressing the outgrowth and excitability of TrkA-positive peptidergic nociceptive neurons and in enhancing the outgrowth and excitability of Ret-positive nonpeptidergic nociceptive neurons.

M. A. Wheeler, D. L. Heffner, S. Kim, S. M. Espy, A. J. Spano, C. L. Cleland, C. D. Deppmann, TNF-α/TNFR1 signaling is required for the development and function of primary nociceptors. Neuron 82, 587–602 (2014). [PubMed]