Frontiers in pruritus research: scratching the brain for more effective itch therapy
Ralf Paus, … , Tamás Bíró, Martin Steinhoff
Ralf Paus, … , Tamás Bíró, Martin Steinhoff
Published May 1, 2006
Citation Information: J Clin Invest. 2006;116(5):1174-1186. https://doi.org/10.1172/JCI28553.
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Review Series

Frontiers in pruritus research: scratching the brain for more effective itch therapy

Abstract

This Review highlights selected frontiers in pruritus research and focuses on recently attained insights into the neurophysiological, neuroimmunological, and neuroendocrine mechanisms underlying skin-derived itch (pruritogenic pruritus), which may affect future antipruritic strategies. Special attention is paid to newly identified itch-specific neuronal pathways in the spinothalamic tract that are distinct from pain pathways and to CNS regions that process peripheral pruritogenic stimuli. In addition, the relation between itch and pain is discussed, with emphasis on how the intimate contacts between these closely related yet distinct sensory phenomena may be exploited therapeutically. Furthermore, newly identified or unduly neglected intracutaneous itch mediators (e.g., endovanilloids, proteases, cannabinoids, opioids, neurotrophins, and cytokines) and relevant receptors (e.g., vanilloid receptor channels and proteinase-activated, cannabinoid, opioid, cytokine, and new histamine receptors) are discussed. In summarizing promising new avenues for managing itch more effectively, we advocate therapeutic approaches that strive for the combination of peripherally active antiinflammatory agents with drugs that counteract chronic central itch sensitization.

Authors

Ralf Paus, Martin Schmelz, Tamás Bíró, Martin Steinhoff

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Figure 1

Table 2 and neurophysiological pathways activated during pruritus (pruritogenic itch).

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Table 2 and neurophysiological pathways activated during pruritus (pruri...
Exogenous or endogenous mediators stimulate specific subtypes of peripheral nerve endings of primary afferent neurons (pruriceptors). High-affinity receptors for pruritogenic mediators transmit the stimulus via intracellular signaling from the periphery to the dorsal root ganglia (DRG) and the spinal cord. Within the spinal cord, itch signals can be modulated (see It is the brain that itches, not the skin). From lamina I, a specific area within the dorsal horn of the spinal cord, the signal is transmitted to the CNS after crossing to the contralateral side (see Figure 3). Activation of specific areas in the CNS results in the perception of itch, leading to discomfort and a scratch response. Additionally, the associated peripheral axon reflex may lead to the release of mast cell–stimulating neuropeptides (e.g., SP), thereby amplifying pruritus via release of histamine, tryptase, and TNF-α, for example (see Table 1). This figure does not consider the interaction between pain and itch fibers on the spinal cord level (see The enigmatic neurophysiology of itch is becoming increasingly understood). Figure modified with permission from The Journal of Investigative Dermatology (5).