The Challenge of Basic Itch Research

Abstract

This paper reviews the basic mechanisms and pathways of itch signaling, emphasizing the progress to date as well as remaining challenges in translating current knowledge to the clinical treatment of chronic itch. Major questions that are addressed include: is itch signaled by a labeled-line pathway separate from that for pain; can alternative theories explain the ability to distinguish between itch and pain; are there specific markers of itch (such as gastrin releasing peptide and its receptor); are there histaminergic and nonhistaminergic itch-signaling pathways? We also address challenges in understanding touch-evoked itch (alloknesis) as a symptom of chronic itch. Basic mechanisms and pathways of itch signaling are reviewed, with an emphasis on the progress to date as well as remaining challenges in translating current knowledge to the clinical treatment of chronic itch. Recent studies reveal 3 subsets of pruriceptive sensory neurons highly expressing itch-related genes. Their fibers project into the spinal cord to activate neurons expressing gastrin releasing peptide (GRP) and its receptor (GRPR), which connect to neurons that express the substance P (NK-1) receptor and project to the parabrachial nucleus and thalamus. Spinal inhibitory interneurons release GABA, glycine and dynorphin to modulate segmental itch transmission. However, nearly all pruriceptive neurons also respond to algogens such as capsaicin. Alternative theories of itch-pain discrimination, such as intensity or spatial contrast, are based on the observation that focal stimulation of nociceptive nerve endings elicits itch while more widespread stimulation elicits pain. These findings cloud the issue of a labeled line for itch-a long-debated but currently unresolved challenge. In higher primates there is a dichotomy of histaminergic and non-histaminergic itch-signaling pathways which is less demarcated in rodents, suggesting species differences. A cardinal symptom of chronic itch is alloknesis, i.e., mechanical or touch-evoked itch. Recent evidence indicates that low-threshold mechanosensory afferents can access the spinal itch pathway, but are normally kept in check by inhibitory interneurons expressing neuropeptide Y (NPY). In chronic itch, NPY-mediated inhibition is reduced, allowing touch to excite itch-signaling pathways. These recent advances provide novel targets for development of therapeutic strategies to relieve chronic itch.

Pruriception and neuronal coding in nociceptor subtypes in human and nonhuman primates

“…In human, cowhage-induced itch and nociceptive sensations are mediated by activation of nociceptive unmyelinated and myelinated afferents that are also thought to mediate pain from noxious heat and mechanical stimuli (Johanek et al, 2008; Namer et al, 2008; Ringkamp et al, 2011; Ringkamp et al, 2013). How the sensations of itch and pain are mediated by activity in the same set of afferent nerve fibers is currently unclear, and several models have been proposed to solve this puzzle (LaMotte et al, 2014; Carstens et al, 2020). Among these, the ‘spatial contrast’ model posits that locally restricted activation of a small population of pruriceptive nociceptors induces itch sensation, while activation of a broader and greater number of nociceptors induces the sensation of pain (Namer et al, 2008; Namer & Reeh, 2013; Steinhoff et al, 2019).…”

“…This would rule out the possibility that these primary sensory neurons constitute labeled-lines that are specifically activated only by pruritic stimuli. Consequently, several different models to explain how pruritic stimuli may be encoded, have been proposed (for review see (LaMotte et al, 2014; Carstens et al, 2020)). Among these, the itch model of ‘spatial contrast’ posits that a pruritic stimulus is signaled by activity in a few nociceptive afferents among other non-active fibers innervating a given skin region (i.e.…”

“…The signaling of pruritic stimuli by nociceptive afferents that are also thought to encode nociceptive mechanical, thermal and chemical stimuli (Ringkamp et al, 2013) poses a conundrum regarding the neuronal coding of these distinct sensations in the nervous system. Among the models that have been proposed to explain this conundrum (for review see (LaMotte et al, 2014; Carstens et al, 2020)), the spatial contrast model posits that neuronal activity from a spatially restricted set of nociceptive afferents is interpreted as ‘itch’, whereas activity from a spatially larger pool of afferents is interpreted as ‘pain’ (Namer et al, 2008; Namer & Reeh, 2013; Steinhoff et al, 2019). However, whether co-activation of different sets of primary afferents by pruritogens that excite different classes of afferents leads to reduced itch and/or increased nociceptive sensation has not been tested in human.…”

How Do Neurons Signal Itch?

“…Electrophysiological data from rodents and monkey did not support a "labeled line" for itch (28,(42)(43)(44) as no specific subpopulation of itch neurons was found. The results rather support the pattern theory of itch according to which nociceptors can signal itch or pain based on the combination of activated fibers resulting in a population coding (1) or based on specific discharge patterns that might differentiate between itch and pain (1).…”

Case Study: Neuropathic Itching Following S3 and S4 Dorsal Root Ganglion Stimulator Trial

“…C-fiber neurons transmit histamine-mediated itch. 3 It is unknown whether there are two independent neural pathways for itch and pain or if they share common pathways. Many of the neurotransmitters involved in pain transmission have also been demonstrated to be involved in the transmission of itch sensation, including tumor necrosis factor, interleukin-1, interleukin-6, Substance P, and prostaglandins.…”