Neurobiology of Itch (Pruritus)


Itch is often defined as an ‘unpleasant sensation that provokes the desire to scratch’. Recent studies have provided novel insights into the molecular mechanisms underlying itch‐selective signalling pathways from the periphery to the central nervous system. Chronic itch is often associated with inflammatory skin diseases such as atopic dermatitis, psoriasis or contact dermatitis, as well as systemic diseases such as renal, cholestatic, hematologic or endocrine pruritus or pruritus related to malignancy, and reduces quality of life. Chronic itch is thought to involve the sensitisation of itch‐signalling pathways, the molecular and cellular processes of which we are just starting to uncover. This review article describes recent findings regarding the basic mechanisms of itch transmission from the skin to the brain. We further describe the neuronal changes that occur both peripherally and centrally under conditions of chronic itch.

Key Concepts

  • There are a variety of endogenous pruritogens and external itch stimuli.
  • Itch transducing channels include TRPV1, TRPA1 and Nav1.7.
  • Spinal excitatory and inhibitory interneurons process itch information.
  • Descending noradrenergic and serotonergic systems modulate spinal itch transmission.
  • Sensitisation occurs in both peripheral and central nervous system under conditions of chronic itch.
  • NK1‐expressing spinal neurons play a major role in itch sensitisation.

Keywords: itch; pruritus; sodium channels; TRP channels; sensitisation; brain; spinal cord; pruriceptors; descending modulation

Figure 1. Schematic drawing of two distinct peripheral nerve terminals of pruriceptors. TRPA1 is activated downstream of GPCRs stimulated by pruritogens other than histamine. TRPV1 is activated downstream of IL31RA/OSMR or H1/H4R stimulated by IL‐31 or histamine, respectively. Both TRP channels produce depolarisation which can open Nav1.7. Action potentials are generated via Nav1.7 to transmit itch signals. Although Nav1.8 is expressed by pruriceptors, a contribution of Nav1.8 to itch is still unknown.
Figure 2. Schematic diagrams of spinal processing of itch (from reference 5, with permission). (a) Itch‐transmitting primary afferent fibres terminate onto NPRA‐expressing excitatory interneurons. GRPR‐expressing excitatory interneurons receive inputs from NPRA‐expressing excitatory interneurons and make synapses (directly or indirectly) onto NK1R‐expressing projection neurons. NK1‐expressing projection neurons receive inhibitory input from Bhlhb5‐originated inhibitory interneurons via dynorphin as well as GABA and glycine. NK1‐expressing spinal neurons also receive polysynaptic input from NK1‐expressing excitatory interneurons that are located in lamina III and transmit touch signals. This pathway is silenced by GABAergic and glycinergic inhibitory interneurons under normal conditions. Whether these inhibitory interneurons originate from Bhlhb5‐expressing spinal neurons is still unknown. (b) Chronic itch leads to sensitisation of itch signalling pathways. Under the condition of chronic itch, NK1‐expressing projection neurons are hyperexcited. A lower activation threshold of NK1‐expressing projection neurons results in spontaneous itch, touch‐evoked itch (alloknesis) and enhanced itch (hyperknesis). Another potential explanation for itch sensitisation is a dysfunction of itch‐inhibitory interneurons. This dysfunction results in disinhibition of NK1‐expressing projection neurons and possibly the polysynaptic touch pathway that sends signals to NK1‐expressing projection neurons Reproduced with permission from Akiyama et al., () © Wolters Kluwer Health, Inc.
Figure 3. The representative brain regions activated by itch stimuli. Brain regions active during itch are indicated by red on three‐dimensional images of brain templates implemented in the MRIcron software (images of brain templates reproduced from Abbreviations: SMA, supplementary motor area; PM, premotor cortex; MI, primary motor cortex; SI, primary somatosensory cortex; SII, secondary somatosensory cortex; Cb, cerebellum; dACC, dorsal part of the anterior cingulate cortex; aMCC, anterior part of the midcingulate cortex; PCC, posterior cingulate cortex; Prec, precuneus; IC: insular cortex.


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Further Reading

Akiyama T and Carstens E (2013) Neural processing of itch. Neuroscience 250: 697–714.

Carstens E and Akiyama T (eds) (2014) Itch: mechanisms and treatment. Boca Raton: CRC Press/ Taylor and Francis, 458 pp.

Cowan A and Yosipovitch G (2015) Pharmacology of itch. Handb Exp Pharmacol. 26: 1–382.

Dhand A and Aminoff MJ (2014) The neurology of itch. Brain. 137 (Pt 2): 313–322.

Kremer AE , Feramisco J , Reeh PW , , Beuers PW , and Oude Elferink RP (2014) Receptors, cells and circuits involved in pruritus of systemic disorders. Biochim Biophys Acta. 1842 (7): 869–892.

LaMotte RH , Dong X and Ringkamp M (2014) Sensory neurons and circuits mediating itch. Nat Rev Neurosci.. 15 (1): 19–31.

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How to Cite close
Akiyama, Tasuku, Mochizuki, Hideki, and Carstens, E(Aug 2015) Neurobiology of Itch (Pruritus). In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025792]