Peripheral Opioid Receptors in the Modulation of Inflammatory Pain: a Narrative Review

Opioid receptors are key modulators of pain, with both central and peripheral subtypes contributing to analgesia. While central opioid receptors have been extensively studied, peripheral opioid receptors, located on sensory nerve terminals and immune cells, have gained attention for their ability to provide localized analgesia and anti-inflammatory effects without central side effects such as respiratory depression and sedation. This narrative review explores the classification, localization, and activation of peripheral opioid receptors, emphasizing their role in inflammatory pain modulation. These receptors are upregulated in inflamed tissues, enhancing analgesic efficacy. Their activation modulates nociceptive signaling through inhibition of excitatory neurotransmitter release, potassium channel activation, and immune regulation. Peripherally acting opioid receptor agonists offer targeted pain relief, while selective antagonists mitigate opioid-induced constipation without affecting central analgesia. Preclinical studies, including carrageenaninduced inflammation models, have reinforced the potential of peripheral opioid receptor targeting in pain therapy. Future research should focus on optimizing these agents for clinical use, improving drug delivery systems, and integrating them into multimodal pain management strategies.