The Challenge of Basic Itch Research
Earl Carstens, Taylor Follansbee, Mirela Iodi Carstens
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.
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 non-histaminergic itch-signaling pathways? We also address challenges in understanding touch-evoked itch (alloknesis) as a symptom of chronic itch.