Barettin, a Nonopioid, Nonhallucinogenic Marine Natural Product with Antihyperalgesic Properties Mediated by 5HT2A Inverse Agonism

Despite increasing interest, there remain limited treatments for chronic pain, with opioids continuing to be one of the top prescribed medications. Marine natural products present a wealth of untapped potential for new treatments for chronic pain. In this study, we investigated the analgesic effects of the sea sponge ligand barettin in a mouse model of chemotherapy-induced peripheral neuropathy (CIPN). Barettin exhibited efficacious antihyperalgesic activity in male mice with no efficacy shown in females. Through the use of a PRESTO-Tango assay, we found that barettin acts as an inverse agonist at the 5HT2A receptor while also presenting no activity at the μ-opioid receptor. Head twitch experiments confirmed no hallucinogenic activity, suggesting that barettin may be a promising nonopioid, nonhallucinogenic, marine-derived therapeutic agent for the treatment of chronic pain.