Identification of Early RET+ Deep Dorsal Spinal Cord Interneurons in Gating Pain

Neuron. 2016 Sep 7;91(5):1137-1153. doi: 10.1016/j.neuron.2016.07.038. Epub 2016 Aug 18.

Abstract

The gate control theory (GCT) of pain proposes that pain- and touch-sensing neurons antagonize each other through spinal cord dorsal horn (DH) gating neurons. However, the exact neural circuits underlying the GCT remain largely elusive. Here, we identified a new population of deep layer DH (dDH) inhibitory interneurons that express the receptor tyrosine kinase Ret neonatally. These early RET+ dDH neurons receive excitatory as well as polysynaptic inhibitory inputs from touch- and/or pain-sensing afferents. In addition, they negatively regulate DH pain and touch pathways through both pre- and postsynaptic inhibition. Finally, specific ablation of early RET+ dDH neurons increases basal and chronic pain, whereas their acute activation reduces basal pain perception and relieves inflammatory and neuropathic pain. Taken together, our findings uncover a novel spinal circuit that mediates crosstalk between touch and pain pathways and suggest that some early RET+ dDH neurons could function as pain "gating" neurons.

MeSH terms

  • Animals
  • Clozapine / analogs & derivatives
  • Clozapine / pharmacology
  • Female
  • Interneurons / drug effects
  • Interneurons / metabolism
  • Interneurons / physiology*
  • Male
  • Mice
  • Mice, Transgenic
  • Neural Inhibition / physiology
  • Neurons / physiology
  • Pain / physiopathology*
  • Pain Measurement
  • Proto-Oncogene Proteins c-ret / metabolism*
  • Spinal Cord / metabolism
  • Spinal Cord / physiology*
  • Spinal Cord Dorsal Horn / metabolism
  • Touch / physiology*

Substances

  • Proto-Oncogene Proteins c-ret
  • Ret protein, mouse
  • Clozapine
  • clozapine N-oxide