Histaminergic itch alone is also complex, with H1 and H4 antagonists reducing some components of itch, whereas H3 receptor antagonists provoke itch ( 12, 13). Itch is clearly more complex than histamine alone. Histamine is an archetypal itch mediator, activated via a G-coupled protein to reduce the activation threshold of an ion channel: TRPV1, which in turn results in calcium influx and release of neuropeptides from sensory nerve fibers ( 11). Many pro-inflammatory compounds from epithelial, neuronal, and inflammatory cells (particularly mast cells, eosinophils, and CD4 lymphocytes) act via their respective G-coupled protein receptors, in combination with factors in the local environment, to lower the activation threshold of TRP channels in the genesis of itch ( 9, 10). Pruritogens either directly or indirectly cause activation of either TRPA1 or TRPV1 ion channels in most cases, or less reported via TRPV4, to lower the activation threshold of itch fibers to generate an action potential ( 8). The transient receptor potential (TRP) channels comprise 28 members in mammals and 27 in humans that are categorized based on amino acid sequence homology, including TRPA, TRPM, and TRPV ( 7). Referred itch occurs when overlapping sensory distribution of nerves or the pathways of nerve activation is coupled with depolarization of the nerve ( 5, 6). The site of itch stimulates local neuropeptide release and can activate neurosensory signals that communicate with the somatosensory and motor cortex, leading to itch localization and cognitive awareness of the itch stimuli ( 1, 3). Neurosensory signals may involve the well-known axon reflex arc, including signaling via the dorsal root ganglion, in addition to local activation and local release of neuropeptides, which is known as the antidromic reflex. Ongoing research suggests co-signaling of pain and itch sharing the same sensory fibers as well as specific itch-signaling sensory fibers, and it is plausible that both mechanisms exist ( 1). Of the C-fibers there are histamine-dependent and histamine-independent pruritogenic fibers ( 4). Itch is detected by nociceptors and free nerve endings, which in turn excite unmyelinated C-fibers and thinly myelinated Aδ nerve fibers ( 3). Most of the literature on the mechanisms and mediators involved in itch is based on our understanding of itch in the skin, also known as pruritoceptive itch, which is generated in the skin by pruritogens either through inflammation via various chemical mediators or skin damage ( 1, 2). This review invites readers to appreciate itch beyond the skin by highlighting several specific itch patterns-nasal, oral, auricular, vulvovaginal, anal, and perineal itch-the pathophysiological mechanisms that underlie them, the clinical patterns these may cause, and some unique treatments. Despite itch being an ancient reflex and evolutionarily conserved phenomenon, better clinical understanding of the nuances between sites of itch sensation may lead to improved clinical outcomes. Less understood and considered are the physiological processes involved in the itching sensation that occurs at mucosal and junctional dermal sites, which is extraordinary as from an evolutionary point of view these sites serve important guardian roles, rich in sensory nerves and inflammatory cells. We traditionally think of itch as a sensation of the skin related to allergy, an insect sting or interestingly, anxiety and frustration. Itch is a nociceptive sensation linked with reflexes and cognitive motor actions. 3Clinical Medicine, Griffith University, Southport, QLD, Australia.2Cingulum Health, Sydney, NSW, Australia.1LifeSpan Medicine, Los Angeles, CA, United States.
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