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Sensory neurons and circuits mediating itch

Nature Reviews Neuroscience volume 15, pages 19–31 (2014)Cite this article

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Key Points

  • Chemicals that cause itch or pain in humans elicit qualitatively different behaviours in animals. Sensory responses and the electrophysiologically recorded responses to these stimuli are used to determine the populations of sensory neurons that transduce and convey the information that the brain uses to produce the sensation of itch and to distinguish itch from pain.

  • Pruritic chemicals elicit action potentials in subsets of cutaneous peripheral nociceptors that also respond with differing sensitivities to one or more types of painful stimuli. Other nociceptors are 'non-pruriceptive' and do not respond to pruritic chemicals but respond to painful capsaicin, heat or mechanical noxious stimuli.

  • In primates, two pruritic agents have been tested extensively: histamine and cowhage spicules. The afferents activated by these agents and other nociceptive afferents convey activity to the spinal dorsal horn, where they activate neurons, including spinothalamic tract (STT) neurons that provide pruriceptive and nociceptive input to the brain.

  • In the monkey, histaminergic and non-histaminergic itch are conveyed by separate subsets of nociceptive STT neurons. In both primary afferents and STT neurons, pruritic stimuli usually activate fewer nociceptive neurons and elicit lower discharge rates than moderately painful or noxious stimuli, thereby providing one means by which the brain could differentiate pruritic from noxious information.

  • In mice, diverse receptor expression and signalling pathways among subsets of pruriceptive and non-pruriceptive nociceptors have been found. Using molecular genetic tools, it was shown that selective activation of Mas-related G-protein-coupled receptor member A3 (MRGPRA3)-expressing neurons induces itch- and not pain-like behaviour, supporting the idea that specific neurons mediate itch.

  • In the dorsal horn, excitatory and inhibitory interneurons have an important role in pruriceptive transmission and several candidate neurotransmitters have been identified. Itch behaviour can be modified by several experimental manipulations and pruritogen-induced activity can be reduced by scratching.

  • Several models have been proposed to explain how the brain might encode itch versus pain. One model suggests that itch depends on more activity in pruriceptive than non-pruriceptive nociceptors. Another model suggests that it is the spatially sparse activation of any type of cutaneous nociceptive neurons that signals itch.

  • Testing the validity of these models will be facilitated in the future by the development of methods to control and manipulate action potential activity independently in pruriceptive and non-pruriceptive neurons.

Abstract

Chemicals that are used experimentally to evoke itch elicit activity in diverse subpopulations of cutaneous pruriceptive neurons, all of which also respond to painful stimuli. However, itch is distinct from pain: it evokes different behaviours, such as scratching, and originates from the skin or certain mucosae but not from muscle, joints or viscera. New insights regarding the neurons that mediate the sensation of itch have been gained from experiments in which gene expression has been manipulated in different types of pruriceptive neurons as well as from comparisons between psychophysical measurements of itch and the neuronal discharges and other properties of peripheral and central pruriceptive neurons.

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Figure 1: Sensory responses to pruritic or painful stimuli.
Figure 2: Pruriceptive neurons are a subset of nociceptive neurons.
Figure 3: Hypothesized cutaneous input to pruriceptive and non-pruriceptive spinothalamic tract neurons in primate.
Figure 4: Pruriceptive neuronal activity matches the time course of itch sensation.
Figure 5: Models of modulation of itch transmission in the dorsal horn.
Figure 6: Secondary dysesthesias in response to pruritic or algesic chemicals.
Figure 7: Representing itch versus pain in the responses of nociceptive neurons.

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Acknowledgements

The authors are supported in part by US National Institutes of Health grants P01 NS47399 P01 NS 047399 (R.H.L. and M.R.) and GM087369 and NS054791 (X.D.)

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Authors and Affiliations

  1. Departments of Anesthesiology and Neurobiology, Yale University School of Medicine, New Haven, 06520–8051, Connecticut, USA

    Robert H. LaMotte

  2. Department of Neuroscience, Johns Hopkins University School of Medicine, 725 N. Wolfe St, Baltimore, 21205, Maryland, USA

    Xinzhong Dong

  3. Department of Neurosurgery, Johns Hopkins University School of Medicine, 600 N. Wolfe St, Baltimore, 21287, Maryland, USA

    Matthias Ringkamp

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PowerPoint slides

Glossary

Noxious stimuli

Stimuli that are overtly or potentially damaging to normal tissues or are normally associated with pain-like (nociceptive) sensations, such as pricking, stinging or burning, that are unpleasant but may or may not hurt.

Nociceptors

High-threshold peripheral receptors or sensory neurons that transduce and encode noxious stimuli.

Pruriceptors

Nociceptors that respond to one or more pruritic chemicals.

Cutaneous receptive fields

Areas of skin within which a stimulus activates a sensory neuron, for example, by evoking action potentials.

Central sensitization

An enhanced responsiveness of nociceptive neurons in the CNS to normal input from peripheral sensory neurons.

'Labelled line' pathway

A pathway serving a particular sensory quality, such as itch. When selectively activated, it will elicit that type of sensation regardless of the type of activating stimulus.

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LaMotte, R., Dong, X. & Ringkamp, M. Sensory neurons and circuits mediating itch. Nat Rev Neurosci 15, 19–31 (2014). https://doi.org/10.1038/nrn3641

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