Essential role of Ret for defining non-peptidergic nociceptor phenotypes and functions in the adult mouse

Eur J Neurosci. 2011 Apr;33(8):1385-400. doi: 10.1111/j.1460-9568.2011.07634.x. Epub 2011 Mar 14.


Transduction of pain following noxious stimuli is mediated by the activation of specialized ion channels and receptors expressed by nociceptive sensory neurons. A common early nociceptive sublineage expressing the nerve growth factor receptor TrkA diversifies into peptidergic and non-peptidergic nociceptors around birth. In this process, peptidergic neurons maintain TrkA expression, while non-peptidergic neurons downregulate TrkA and upregulate the common glial-derived neurotrophic factor family ligand receptor Ret and bind the isolectin B4 (IB4). Although Ret can have profound impacts on the molecular and physiological properties of nociceptive neurons, its role is not fully understood. Here we have deleted Ret in small- and medium-size sensory neurons, bypassing the early lethality of the full Ret knockout. We identify that Ret is expressed in two distinct populations of small-medium sized non-peptidergic neurons, an IB4(+) and an IB4(-) population. In these neurons, Ret is a critical regulator of several ion channels and receptors, including Nav1.8, Nav1.9, ASIC2a, P2X3, TrpC3, TrpM8, TrpA1, delta opioid receptor, MrgD, MrgA1 and MrgB4. Ret-deficient mice fail to respond to mustard oil-induced neurogenic inflammation, have elevated basal responses and a failure to terminate injury-induced sensitization to cold stimuli, hypersensitivity to basal but not injury-induced mechanical stimuli, while heat sensation is largely intact. We propose that elevated pain responses could be contributed by GPR35, which is dysregulated in adult Ret-deficient mice. Our results show that Ret is critical for expression of several molecular substrates participating in the detection and transduction of sensory stimuli, resulting in altered physiology following Ret deficiency.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / physiology
  • Biomarkers / metabolism
  • Female
  • Ganglia, Spinal / cytology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nociceptors / cytology
  • Nociceptors / physiology*
  • Pain Measurement
  • Phenotype
  • Proto-Oncogene Proteins c-ret / genetics
  • Proto-Oncogene Proteins c-ret / metabolism*
  • Receptor, trkA / genetics
  • Receptor, trkA / metabolism
  • Signal Transduction / physiology
  • Temperature
  • Touch / physiology
  • Touch Perception / physiology


  • Biomarkers
  • Proto-Oncogene Proteins c-ret
  • Receptor, trkA
  • Ret protein, mouse