717 Peripheral blockade of T-type calcium channels by DX416 inhibits acute itch and modulates immune response

      The processing of itch and pain signals is regulated by many different ion channels. Among those are T-type calcium channels which are important regulators that contribute to the firing behavior of itch and pain sensing neurons. The human genome encodes three different T-type channels: Cav3.1, Cav3.2, Cav3.3. It has been shown recently that pharmacological blockade of T-type calcium channels yielded an inhibition in acute itch. Systemic T-type inhibitors are currently under development to treat pain. We hypothesize that a topical treatment that selectively inhibits Cav3.1 and Cav3.2 in the skin will decrease both cutaneous signal input that triggers itch, and at the same time will decrease local inflammatory immune responses potentiating itch. Together, this will result in the reduction of itch with improved efficacy and limited systemic exposure leading to reduced risk of adverse effects compared to systemic treatments. We have found that cannabinoid CB2 agonists inhibit T-type channels. We have used this information to develop a new cannabinoid-based T-type channel inhibitor DX416, which inhibits the function of Cav3.1 and Cav3.2 and devoid of cannabinoid receptors affinity in vitro with high specificity and potency. Remarkably, local administration of DX416 results in an inhibition of histamine-induced acute itch in mouse models without impairing motor function. Furthermore, DX416 treatment results in a pronounced reduction of inflammatory mediators, such as TNFα, during acute inflammation modeled through in vitro stimulation of human peripheral blood monocytes and THP-1 derived antigen presenting cells. Collectively, our data revealed that Cav3.1 and Cav3.2 blockade may represent a promising therapeutic strategy for the inhibition of itch and concurrent acute inflammation.