c-Jun/p38MAPK/ASIC3 pathways specifically activated by nerve growth factor through TrkA are crucial for mechanical allodynia development

Pain. 2020 May;161(5):1109-1123. doi: 10.1097/j.pain.0000000000001808.

Abstract

Mechanical allodynia is a cardinal sign of several inflammatory pain disorders where nerve growth factor, a prototypic neurotrophin, plays a crucial role by binding to TrkA receptors. Here, we took the advantage of our generated knock-in mouse model expressing a chimeric TrkA/TrkC receptor that seems to not specifically develop mechanical allodynia after inflammation, to identify the TrkA downstream pathways involved in this phenomenon. We confirmed and extended that disrupting TrkA-specific pathways leads to a specific deficit in mechanical hypersensitivity development after somatic (systemic nerve growth factor administration and paw incision) and, to a lesser extent, visceral injuries. Despite a deficit in thin, mainly peptidergic, fibre innervation in TrkAC mice, thermal hyperalgesia development was not different from WT mice. Inflammatory reaction (oedema, IL-6 content), pain behaviours after intraplantar capsaicin, as well as TRPV1 calcium imaging response of dorsal root ganglion neurons were similar between TrkAC and WT mice. This deficiency in mechanical allodynia development in TrkAC mice is likely due to the alteration of the expression of different TrkA transduction pathways (ie, Akt, p38 MAPK, and c-Jun) especially p38 MAPK, in the dorsal root ganglion cell bodies, ultimately leading to an alteration of at least, ASIC3 channel overexpression, known to participate in nociceptor mechanosensory function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ganglia, Spinal
  • Hyperalgesia*
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Signaling System
  • Mice
  • Nerve Growth Factor / genetics
  • Receptor, trkA / genetics
  • Receptor, trkC
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Nerve Growth Factor
  • Receptor, trkA
  • Receptor, trkC
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases