Although eugenol is widely used in dentistry, little is known about the molecular mechanisms responsible for its anesthetic properties. In addition to calcium channels, recently demonstrated by our group, there could be another molecular target for eugenol. Using a whole-cell patch-clamp technique, we investigated the effect of eugenol on voltage-gated sodium channel currents ( I_Na) in rat dental primary afferent neurons identified by retrograde labeling with a fluorescent dye in maxillary molars. Eugenol inhibited action potentials and I_Nain both capsaicin-sensitive and capsaicin-insensitive neurons. The pre-treatment with capsazepine, a competitive antagonist of transient receptor potential vanilloid 1 (TRPV1), failed to block the inhibitory effect of eugenol on I_Na, suggesting no involvement of TRPV1. Two types of I_Na, tetrodotoxin (TTX)-resistant and TTX-sensitive I_Na, were inhibited by eugenol. Our results demonstrated that eugenol inhibits I_Nain a TRPV1-independent manner. We suggest that I_Nainhibition by eugenol contributes to its analgesic effect.

Significance: Transient receptor potential melastatin type 2 (TRPM2) is an oxidative stress-sensing calcium-permeable channel that is thought to contribute to the calcium influx associated with neurodegenerative diseases. Here we show that TRPM2 deficiency lowers chronic unpredictable stress (CUS)-induced reactive oxygen species (ROS) and calpain activation and prevents aberrant hyperactivation of cyclin-dependent kinase 5 (Cdk5). In mice models of CUS, genetic elimination of TRPM2 normalized behavioral deficits. Moreover, removal of Cdk5 reversed the antidepressant-like behaviors observed in Trpm2 ^−/− mice. Our results reveal the important roles of TRPM2 in raising ROS levels and aberrantly hyperactivating Cdk5 in mouse models of CUS and suggest that TRPM2 could be a target for treating ROS-induced neurodegenerative diseases such as depression.

Psoriasis is inflammatory skin disease associated with itch, a troublesome symptom with few therapeutic options. Transient receptor potential channel 4 (TRPC4) is highly expressed in dorsal root ganglia (DRGs). Recently, we have revealed a previously unknown itch signaling in DRG neurons by which TRPC4 mediates itch to serotonergic antidepressants, and demonstrated the antipruritic effect of the TRPC4 inhibitor ML204. However, the role of TRPC4 in acute and chronic itch is still largely unknown. Here, we have characterized the expression of TRPC4 in peptidergic DRG neurons and showed that acute itch induced by serotonin and histamine was attenuated in TRPC4 knockout (TRPC4 KO) mice and mice treated with ML204. We also showed that silencing TRPC4 in DRG and its inhibition by intradermal injections were also effective in decreasing psoriatic itch after repeated applications of imiquimod (IMQ), a preclinical model of psoriasis. Of clinical relevance, intradermal injections of ML204 in psoriasiform skin significantly reversed IMQ-established chronic itch and cutaneous inflammation. Given that TRPC4 is expressed in human DRGs and a specific inhibitor is in clinical trials, our data not only expand our understanding of itch and psoriasis, but also reveal TRPC4 as a potential therapeutic target with considerable translational benefit.