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The neurobiology of itch

Key Points

  • The mechanisms of chronic itch conditions have yet to be fully clarified, and therefore itch is clinically classified according to the underlying diseases originating in the skin, which are either systemic or directly damage neurons.

  • Antagonistic interactions between itch and pain underlie the suppression of itch by inducing pain through scratching, but also itch that is evoked by opioid analgesics. Therapeutically, opioid antagonists have shown antipruritic efficacy.

  • Similar patterns of peripheral neuronal sensitization and nerve fibre sprouting have been found in both chronic itch and chronic pain conditions. Nerve growth factor (NGF) has emerged as a possible underlying mediator. Therefore, anti-NGF strategies are promising as antipruritic and analgesic therapies.

  • Symptoms of central sensitization are strikingly similar between itch (allodynia versus punctate hyperalgesia) and pain (alloknesis versus punctate hyperknesis). The antipruritic efficacy of classical analgesics for neuropathic pain (for example, gabapentin and antidepressants) also suggests common underlying mechanisms for neuropathic pain and itch.

  • A broad overlap of receptor systems exists between pain and itch, including protease-activated receptors (PARs) and transient receptor potential receptor vanilloid type 1 (TRPV1). Apart from histamine H1 receptors, new candidates for pruritus-specific mediator systems are interleukin-31 and H4 receptors.

  • Keratinocytes might contribute to pruritus not only by releasing sensitizing mediators, such as NGF, but also through their involvement in the transduction process through their TRPV1, TRPV3 and TRPV4 receptors.

  • A distinct neuronal pathway for itch consisting of histamine-sensitive mechano-insensitive primary afferent C-fibres and spino-thalamic projection neurons has been identified that can explain some, but not all, subtypes of itch. Mechanically-, electrically- or cowhage-induced itch is not mediated by this fibre class, which indicates the existence of additional, as yet to be characterized, pruriceptive nerve fibre classes.

  • Central imaging has identified similar areas as being involved in acute itch and pain processing, including the dorsal posterior insula, anterior cingulated and prefrontal cortices, as well as the thalamus and premotor areas. More pronounced ipsilateral activation of motor areas in itch might relate to the planning of a scratch response.

  • Clinically important, itch not only has aversive dimensions, but also has a hedonic component, which might be a key driver for compulsive scratching.

Abstract

The neurobiology of itch, which is formally known as pruritus, and its interaction with pain have been illustrated by the complexity of specific mediators, itch-related neuronal pathways and the central processing of itch. Scratch-induced pain can abolish itch, and analgesic opioids can generate itch, which indicates an antagonistic interaction. However, recent data suggest that there is a broad overlap between pain- and itch-related peripheral mediators and/or receptors, and there are astonishingly similar mechanisms of neuronal sensitization in the PNS and the CNS. The antagonistic interaction between pain and itch is already exploited in pruritus therapy, and current research concentrates on the identification of common targets for future analgesic and antipruritic therapy.

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Figure 1: Mediators and the sensitization pattern of nociceptive and pruriceptive neurons.
Figure 2: Activation patterns of primary afferent fibres and spinal projection neurons in response to itch or pain sensation evoked by iontophoresis of histamine.
Figure 3: Activated brain areas in pain and itch as assessed by central imaging.

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Glossary

Central sensitization

Plastic changes in the CNS (adaptive or pathological) that lead to enhanced responses and/or lower thresholds.

Allodynia

The perception of a stimulus as painful when previously the same stimulus was reported to be non-painful.

Punctate hyperalgesia

Type of central sensitization for pain in which the pain elicited by punctate mechanical stimuli is more prolonged and stronger than normally experienced.

Alloknesis

Type of central sensitization for itch in which touch triggers the sensation of itch.

Punctate hyperknesis

Type of central sensitization for itch in which the itch evoked by punctate mechanical stimuli is more prolonged and stronger than normally experienced.

Iontophoresis

A non-invasive method of propelling high concentrations of a charged substance, normally medication or bioactive-agents, transdermally by repulsive electromotive force using a small electrical charge applied to an iontophoretic chamber containing a similarly charged active agent and its vehicle.

Positron emission tomography

(PET). In vivo imaging technique used for diagnostic examination that involves the acquisition of physiological images based on the detection of positrons, which are emitted from a radioactive substance previously administered to the patient.

Functional MRI

(fMRI). Technique that allows the spatial investigation of central neuronal activation by the measurement of the secondary increase of perfusion following neuronal activity.

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Ikoma, A., Steinhoff, M., Ständer, S. et al. The neurobiology of itch. Nat Rev Neurosci 7, 535–547 (2006). https://doi.org/10.1038/nrn1950

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