Osthole inhibits histamine-dependent itch via modulating TRPV1 activity

Itch (pruritus) is an unpleasant cutaneous sensation1, and is also a symptom of many common diseases, including atopic dermatitis, thyroid diseases, diabetes mellitus, chronic renal failure, and cholestatic liver diseases2. People with chronic pruritus experience decreased quality of life due to sleeplessness, anxiety, depression, and embarrassment3. Histamine—one of the best known pruritogens—is the mediator in several conditions such as urticaria, insect bite reactions, cutaneous mastocytosis, and drug rashes4. Itch is often classified into histamine-dependent and histamine-independent itch. Histamine receptors are members of the G protein-coupled receptors (GPCR). Four subtypes of histamine receptors (H1–H4) have been identified5. Several studies found that histamine H1 and H4 receptors play a critical role in histamine-induced itch6. Histamine H3 receptor, as a presynaptic auto- and heteroreceptor, regulates histamine synthesis and release in the central and peripheral nervous system7; however, the involvement of histamine H2 receptor in histamine-dependent itch is not convincing6. TRPV1—a nonselective cation channel stimulated by capsaicin, heat, and H+—has been implicated in mediation of pain and itch8,9. The TRPV1 channel is modulated by GPCR signalings10. Most pruritogens can activate GPCRs and trigger itch by activating the TRP channels, including TRPV19. A growing body of evidence indicates that H1R is coupled with Gq/G11 to active phospholipase Cβ3 (PLCβ3), resulting in the increase of intracellular Ca2+ in DRG neurons via TRPV111. Histamine also activates TRPV1 via the PLA2/LO pathway, leading to the excitation of sensory neurons to induce itch12. In addition, TRPV1−/− mice showed significantly attenuated scratching behavior after injection of trypsin13. These findings suggest that TRPV1 plays a critical role in histamine-dependent itch, especially in H1 receptor-mediated itch. Cnidii monnieri fructus (dried fruit of Cnidium monnieri [L.] Cusson), as an herbal medicine, functions in anti-allergic, anti-dermatophytic, anti-cancer, killing parasites, and in anti-itch14. Cnidium monnieri fructus has been used for centuries in traditional Chinese medicine to treat various diseases such as sexual dysfunction, asthma, osteoporosis, and skin ailments15. The main constituents of Cnidium monnieri are coumarins, such as osthole, imperatorin, bergapten, isopimpinellin, and xanthotoxin, which have various biological activities16. It has been reported that osthole (7-methoxy-8 –isopentenoxycoumarin, Fig. 1) has anti-inflammatory, anti-osteoporotic, anti-tumor, and estrogen-like effects17,18,19,20,21. Osthole also has an antipruritic effect in allergic model animals22. Matsuda, H. et al. reported that ethanol extract of Cnidii Monnieri Fructus including osthole showed an inhibitory effect on compound 48/80-induced scratching behavior23. The precise role of osthole in the histamine-dependent itch, however, is unclear and the molecular mechanism of its anti-pruritic effect is underappreciated. Figure 1 Chemical structure of osthole. In the current study, we sought to explore whether osthole inhibits histamine-dependent itch via TRPV1. Our results showed that osthole clearly reduced the scratching behaviors induced by histamine. Osthole also suppressed the H1 and H4 receptor-mediated scratching behaviors. Furthermore, osthole decreased the response of DRG neurons to histamine, HTMT, VUF8430, and capsaicin by modulating the TRPV1 activity.