Superoxide Anion Generation, Its Pathological Cellular and Molecular Roles and Pharmacological Targeting in Inflammatory Pain: Lessons from the Potassium Superoxide Model

Reactive oxygen species (ROS) are formed by the incomplete reduction of oxygen and play a crucial role in both physiological function and pathological process, being controlled by enzymatic and non-enzymatic antioxidant systems. However, excessive ROS production can exceed the body’s antioxidant capacity, resulting in oxidative stress and causing cell death and oxidation of important biomolecules. In this context, the inhibition and/or modulation of ROS has been shown to be effective in reducing pain, oxidative stress, and inflammation. Among ROS, superoxide anion (O2•−) is the first free radical to be formed through the mitochondrial electron transport chain (ETC) or by specific enzymes systems, such as the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) complex. O2•− plays a significant role in the development and maintenance of pain associated with inflammatory conditions through direct or indirect activation of primary nociceptive neurons and, consequently, peripheral and central sensitization. Experimentally, potassium superoxide (KO2, a O2●− donor) is used to initiate O2●− mediated inflammatory and nociceptive responses, making it important for studying the mechanisms associated with ROS-induced pain and evaluating potential therapeutic molecules. This review addresses the production and regulation of O2•−, highlighting its biosynthesis, redox control, and its physiological and pathological roles in the development of inflammatory pain, as well as the pharmacological therapies under development aimed at its generation and/or action.