Phlorotannins from edible marine seaweed Ecklonia stolonifera disrupt USP5-Cav3.2 calcium channel interactions and reverse chronic inflammatory pain

Ecklonia stolonifera is an edible marine seaweed that contains a high amount of phlorotannins, including phlorofucofuroeckol A (PFFA) and dieckol that have a range of pharmacologic effects. Here we report that these two phlorotannins block the interactions between the deubiquitinase USP5 and the Cav3.2 T-type calcium channel which we previously identified as a unique molecular target for pain. PFFA and dieckol delivered intrathecally (10 μg/i.t.) or intragastrically (30 mg/kg, p.o.) inhibited both phases of formalin-induced nocifensive behaviors and eliminated thermal hyperalgesia in a chronic inflammatory pain model induced by administering complete Freund's adjuvant (CFA) to the hind paws of male and female mice. Dieckol but not PFFA lost its analgesic effects in Cav3.2 null mice treated with CFA, suggesting that Cav3.2 channels are not essential for the in vivo actions of PFFA, but are required for those exerted by dieckol. Overall, our results suggest that phlorotannins derived from edible marine seaweeds, particularly PFFA, could be a novel class of analgesics that target the Cav3.2/USP5 interaction.