Decoding the mechanism of proanthocyanidins in central analgesia: redox regulation and KCNK3 blockade

Abstract

Neuropathic pain causes enduring physical discomfort and emotional distress. Conventional pharmacological treatments often provide restricted relief and may result in undesirable side effects, posing a substantial clinical challenge. Peripheral and spinal redox homeostasis plays an important role in pain processing and perception. However, the roles of oxidative stress and antioxidants in pain and analgesia on the cortical region during chronic pain remains obscure. Here we focus on the ventrolateral orbital cortex (VLO), a brain region associated with pain severity and involved in pain inhibition. Using a spared nerve injury mouse model, we observed the notable reactive oxygen species (ROS)-mediated suppression of the excitability of pyramidal cells (PYRVLO) in the VLO. Nasal application or microinjection of the natural antioxidants proanthocyanidins (PACs) to the VLO specifically increased the activity of PYRVLO and induced a significant analgesic effect. Mechanistically, PACs activate PYRVLO by inhibiting distinct potassium channels in different ways: (1) by scavenging ROS to reduce ROS-sensitive voltage-gated potassium currents and (2) by acting as a channel blocker through direct binding to the cap structure of KCNK3 to inhibit the leak potassium current (Ileak). These results reveal the role of cortical oxidative stress in central hyperalgesia and elucidate the mechanism and potential translational significance of PACs in central analgesia. These findings suggest that the effects of PACs extend beyond their commonly assumed antioxidant or anti-inflammatory effects. Neuropathic pain is a challenging condition that affects the nervous system, causing abnormal sensations and heightened sensitivity. Researchers explored the potential of proanthocyanidins, natural antioxidants found in plants, to alleviate neuropathic pain. The study involves experiments on mice with nerve injuries to mimic neuropathic pain. Researchers administered proanthocyanidins to the ventrolateral orbitofrontal cortex, a key brain region for pain regulation. They measured pain responses and examined brain activity using various techniques, including electrode recordings and molecular analysis. Results showed that proanthocyanidins decreased pain sensitivity in mice by lowering oxidative stress and modulating specific potassium channels that help control nerve cell activity. This dual mechanism—antioxidant effects and potassium channel regulation—highlights proanthocyanidins as an alternative to conventional pain treatments. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.