Differential Coding of Itch and Pain by a Subpopulation of Primary Afferent Neurons

Neuron. 2020 Jun 17;106(6):940-951.e4. doi: 10.1016/j.neuron.2020.03.021. Epub 2020 Apr 15.


Itch and pain are distinct unpleasant sensations that can be triggered from the same receptive fields in the skin, raising the question of how pruriception and nociception are coded and discriminated. Here, we tested the multimodal capacity of peripheral first-order neurons, focusing on the genetically defined subpopulation of mouse C-fibers that express the chloroquine receptor MrgprA3. Using optogenetics, chemogenetics, and pharmacology, we assessed the behavioral effects of their selective stimulation in a wide variety of conditions. We show that metabotropic Gq-linked stimulation of these C-afferents, through activation of native MrgprA3 receptors or DREADDs, evokes stereotypical pruriceptive rather than nocifensive behaviors. In contrast, fast ionotropic stimulation of these same neurons through light-gated cation channels or native ATP-gated P2X3 channels predominantly evokes nocifensive rather than pruriceptive responses. We conclude that C-afferents display intrinsic multimodality, and we provide evidence that optogenetic and chemogenetic interventions on the same neuronal populations can drive distinct behavioral outputs.

Keywords: C-fibers; MrgprA3; P2X3; chemogenetics; chloroquine; nociception; optogenetics; pruritus; somatosensation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Adenosine Triphosphate
  • Animals
  • Channelrhodopsins / metabolism*
  • Chloroquine
  • Ganglia, Spinal / metabolism
  • Gastrin-Releasing Peptide / metabolism
  • Light
  • Mice
  • Nerve Fibers, Unmyelinated / metabolism*
  • Neurons, Afferent / metabolism*
  • Neurons, Afferent / physiology
  • Nociception / physiology*
  • Optogenetics
  • Pain / metabolism*
  • Pruritus / metabolism*
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, Opioid / metabolism
  • Receptors, Purinergic P2X3 / metabolism*
  • Transient Receptor Potential Channels / metabolism


  • Channelrhodopsins
  • MrgprA3 protein, mouse
  • Receptors, G-Protein-Coupled
  • Receptors, Opioid
  • Receptors, Purinergic P2X3
  • Transient Receptor Potential Channels
  • Gastrin-Releasing Peptide
  • Chloroquine
  • Adenosine Triphosphate

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