Molecular Mechanisms of Itch Sensations

Itch is a sensation which causes scratching response to protect skin against external harmful reagents. Acute itch arises in short time period after insect bites or allergen contact. Chronic itch happens in various skin diseases such as atopic dermatitis: AD) and psoriasis. Chronic itch usually continues for over six weeks and is resistant to commonly used anti-histamine drugs. While pain has caught an early attention due to its severity, the molecular mechanism of itch has not been studied in detail. Itch and pain share common features because they are transmitted by similar neuronal circuits. However, itch is a distinct somatosensation and has opposite characteristics to pain. Itch elicits scratching but pain causes withdrawal reflex. Interestingly, minor pain induced by scratching reduces itch and suppression of pain by opioid analgesics such as morphine elicits itch as a side effect. Despite recent advances, our understanding about itch sensory mechanisms is still primitive. Gastrin-releasing peptide receptor: GRPR) was identified as the first itch-specific receptor in the spinal cord. GRPR cell ablation by bombesin-saporin abolished general scratching responses to pruritogens. Because GRPR mutant mice still have remained itch responses, it is possible that additional itch mediators are present in the spinal GRPR neurons. Differential screening and pharmacological or small interfering RNA: siRNA) approach identified four histamine-independent: Atp2a1, Pld3, Pacsin3 and Itpr3), three histamine-dependent: S100a8, CALR and DSP) and one both-dependent: TRPV4) itch genes. Atp2a1 and Itpr3 were selected for further characterization. Atp2a1 and Itpr3 are involved in GRPR downstream Ca2+ signaling pathway for histamine-independent itch. GRPR is also expressed in peripheral tissues such as dorsal root ganglia: DRG) and skin in addition to the spinal cord. Gastrin-releasing peptide: GRP) intradermal: i.d.) injection induces dose-dependent scratching responses that are abolished in GRPR mutant mice. Peripheral: intraperitoneal: i.p.) and i.d.) application of GRPR antagonists inhibits chloroquine: CQ), GRP and allergic contact dermatitis: ACD)-induced scratching responses in mice. It is interesting to find peripheral GRPR functions for itch sensation because it will provide an alternative therapeutic route for itch by targeting peripheral GRPR activities rather than spinal cord GRPR. This also can circumvent potential side effects in central nervous system: CNS) by intrathecal: i.t.) injections. TRPV4 was identified as a crucial itch mediator in DRG for both histamine-dependent and -independent itch by siRNA screening. TRPV4 is co-expressed with multiple pruritic genes such as GRP, transient receptor potential vanilloid 1: TRPV1), mas-related G-protein coupled receptor A3: MrgprA3) and histamine receptor 1: H1R). TRPV4-/- mice showed reduced scratching responses in CQ and histamine-induced pruritic models. siRNA i.t. injection efficiently reduced TRPV4 expression in DRG and decreased both types of itch consistently. i.t. application of endogenous TRPV4 agonist, 5, 6-epoxyeicosatrienoic acid: 5, 6-EET), caused scratching responses that were significantly attenuated in TRPV4-/- mice. Interestingly, TRPV4-/- mice had reduced scratching responses in ACD mice model without affecting on skin inflammation. TRPV4 expression was up-regulated in ACD mice DRG suggesting that an increased TRPV4 activity may be responsible for the aggravated chronic itch. Ca2+ imaging with DRG culture further confirmed that TRPV4 activation is functionally involved in itch sensory transmission in peripheral neurons. TRPV4 in DRG will be a good candidate for treatment of ACD-related chronic itch. Characterization of GRPR-mediated itch mechanisms and identification of novel itch-specific genes will provide basic understanding about itch sensory mechanism and pioneering work for future itch studies such as identifying potential itch therapeutic targets