How Do Neurons Signal Itch?

Abstract

Mechanistic theories of itch are based on neuronal specificity, stimulus intensity, and temporal or spatial discharge patterns. Traditionally, these theories are conceptualized as mutually exclusive, assuming that finding evidence for one theory would exclude the others and could sufficiently explain itch. Current experimental data primarily support the specificity or pattern theory of itch. However, in contrast to an assumed inherent exclusivity, recent results have shown that even within itch-specific pathways in the spinal cord, temporal discharge patterns are important as sustained pruriceptor is required to allow successful transsynaptic signal progression. Also, optogenetic activation of pruriceptors suggest that the combination of neuronal specificity and temporal pattern determines the sensory effect: tonic activation of pruriceptors is required to induce scratching behavior whereas short-lasting stimulation rather causes withdrawal. In addition to the mere duration of discharge, also the temporal pattern or spatial aspects could critically contribute to elicit pruritus instead of pain. Basic neurophysiological studies trying to validate neuronal theories for pruritus in their pure form provide unitary concepts leading from neuronal discharge to the itch sensation. However, the crucial clinical questions have the opposite perspective: which mechanisms explain the chronic itch in a given patient or a given disease? In trying to solve these clinical problems we should not feel bound to the mutual exclusive nature of itch theories, but rather appreciate blending several theories and also accept combinations of itch and pain. Thus, blended versions of itch theories might better suffice for an explanation of chronic itch in patients and will improve the basis for mechanistic treatment options.

Dysregulated Expression of Ion Channels in Sensory Neurons Enhances Action Potential Afterhyperpolarization in Patients with Chronic Kidney Disease–Associated Pruritus

“…A variety of receptors involved in AP generation help discriminate between pain and pruritus sensations, possibly depending on their spatial locations, distribution patterns, morphology, and other properties. Our findings suggest that temporal discharge patterns of APs are key components underlying pruritus, thereby supporting the spatial contrast theory [46]. Differential expression of ICs is likely to contribute functional diversity to sensory neuron signaling.…”

The expression of ion channels in sensory neurons that can shift action potential in direction to hyperpolarization are dysregulated in patients with chronic kidney disease–associated pruritus

“…A variety of receptors involved in AP generation help discriminate between pain and pruritus sensations, possibly depending on their spatial locations, distribution patterns, morphology, and other properties. Our ndings suggest that temporal discharge patterns of APs are key components underlying pruritus, thereby supporting the spatial contrast theory [44]. Differential expression of ICs is likely to contribute functional diversity to sensory neuron signaling.…”

Microinjection of pruritogens in NGF-sensitized human skin

“…In contrast to intradermal microinjection of the TRPV1 agonist capsaicin, which causes pain, focal capsaicin administration induces itch of similar intensity as histamine 10 or BAM8–22 5 . Specific discharge patterns evoked by either pruritic or algetic stimuli, particular neuronal population codes or a combination of both are currently the favored models to explain how exactly non-histaminergic itch is encoded in humans and can be differentiated from pain 11 .…”