Caffeic acid exhibits anti-pruritic effects by inhibition of multiple itch transmission pathways in mice.

Itch is an unpleasant sensation that evokes a desire to scratch. Although often regarded as a trivial 'alarming' sensation, itch may be debilitating and exhausting, leading to reduction in quality of life. In the current study, the question of whether caffeic acid can be used to alleviate itch sensation induced by various pruritic agents, including histamine, chloroquine, SLIGRL-NH2, and β-alanine was investigated. It turned out that histamine-induced intracellular calcium increase was significantly blocked by caffeic acid in HEK293T cells that express H1R and TRPV1, molecules required for transmission of histamine-induced itch in sensory neurons. In addition, inhibition of histamine-induced intracellular calcium increase by caffeic acid was demonstrated in primary cultures of mouse dorsal root ganglion (DRG). When chloroquine, an anti-malaria agent known to induce histamine-independent itch - was used, it was also found that caffeic acid inhibits the induced response in both DRG and HEK293T cells that express MRGPRA3 and TRPA1, underlying molecular entities responsible for chloroquine-mediated itch. Likewise, intracellular calcium changes by SLIGRL-NH2 - an itch-inducing agent via PAR2 and MRGPRC11 - were decreased by caffeic acid as well. However, it was found that caffeic acid is not capable of inhibiting β-alanine-induced responses via its specific receptor MRGPRD. Finally, in vivo scratching behavior tests showed that caffeic acid indeed has anti-scratching effects against histamine, chloroquine, and SLIGRL-NH2 administration but not by β-alanine. Overall, the current study demonstrated that caffeic acid has anti-itch effects by inhibition of multiple itch mechanisms induced by histamine, chloroquine and SLIGRL-NH2.

Pradhananga S ，Shim WS 《-》

TRPV1 and TRPA1 Channels Are Both Involved Downstream of Histamine-Induced Itch.

Wilzopolski J ，Kietzmann M ，Mishra SK ，Stark H ，Bäumer W ，Rossbach K ... -  《Biomolecules》

Involvement of TRPV4 in Serotonin-Evoked Scratching.

Several thermosensitive transient receptor potential channels (transient receptor potential vanilloid type-1, -3; transient receptor potential cation channel, subfamily A, member 1) have been implicated in itch. In contrast, the role of transient receptor potential vanilloid type-4 (TRPV4) in itch is unknown. Therefore, we investigated if TRPV4, a temperature-sensitive cation channel, plays an important role in acute itch in mice. Four different pruritogens, including serotonin (5-hydroxytryptamine [5-HT]), histamine, SLIGRL (protease-activated receptors 2/mas-related G-protein-coupled receptor C11 agonist), and chloroquine (mas-related G-protein-coupled receptor A3 agonist), were intradermally injected into mice and itch-related scratching behavior was assessed. TRPV4 knockout mice exhibited significantly fewer 5-HT-evoked scratching bouts compared with wild-type mice. Notably, no differences between TRPV4 knockout and wild-type mice were observed in the number of scratch bouts elicited by SLIGRL and histamine. Pretreatment with a TRPV4 antagonist significantly attenuated 5-HT-evoked scratching in vivo. Using calcium imaging in cultured primary murine dorsal root ganglion neurons, the response of neurons after 5-HT application, but not other pruritogens, was significantly lower in TRPV4 knockout compared with wild-type mice. A TRPV4 antagonist significantly suppressed 5-HT-evoked responses in dorsal root ganglion cells from wild-type mice. Approximately 90% of 5-HT-sensitive dorsal root ganglion neurons were immunoreactive for an antibody to TRPV4, as assessed by calcium imaging. These results indicate that 5-HT-induced itch is linked to TRPV4.

Akiyama T ，Ivanov M ，Nagamine M ，Davoodi A ，Carstens MI ，Ikoma A ，Cevikbas F ，Kempkes C ，Buddenkotte J ，Steinhoff M ，Carstens E ... -  《-》

Protein kinase Cδ mediates histamine-evoked itch and responses in pruriceptors.

Valtcheva MV ，Davidson S ，Zhao C ，Leitges M ，Gereau RW 4th ... -  《Molecular Pain》

TRPA1 is required for histamine-independent, Mas-related G protein-coupled receptor-mediated itch.

Wilson SR ，Gerhold KA ，Bifolck-Fisher A ，Liu Q ，Patel KN ，Dong X ，Bautista DM ... -  《-》