Small organic molecule disruptors of Cav3.2-USP5 interactions reverse inflammatory and neuropathic pain

Background: Cav3.2 channels facilitate nociceptive transmission and are upregulated in DRG neurons in response to nerve injury or peripheral inflammation. We reported that this enhancement of Cav3.2 currents in afferent neurons is mediated by deubiquitination of the channels by the deubiquitinase USP5, and that disrupting USP5/Cav3.2 channel interactions protected from inflammatory and neuropathic pain. Results: Here we describe the development of a small molecule screening assay for USP5-Cav3.2 disruptors, and report on two hits of a similar to 5000 compound screen - suramin and the flavonoid gossypetin. In mouse models of inflammatory pain and neuropathic pain, both suramin and gossypetin produced dose-dependent and long-lasting mechanical anti-hyperalgesia that was abolished or greatly attenuated in Cav3.2 null mice. Suramin and Cav3.2/USP5 Tat-disruptor peptides were also tested in models of diabetic neuropathy and visceral pain, and provided remarkable protection. Conclusions: Overall, our findings provide proof of concept for a new class of analgesics that target T-type channel deubiquitination.