In this review, we discuss the importance of capsaicin to the current understanding of neuronal modulation of pain and explore the mechanisms of capsaicin-induced pain. We will focus on the analgesic effects of capsaicin and its clinical applicability in treating pain. Furthermore, we will draw attention to the rationale for other clinical therapeutic uses and implications of capsaicin in diseases such as obesity, diabetes, cardiovascular conditions, cancer, airway diseases, itch, gastric, and urological disorders.

Pathological pain can be initiated after inflammation and/or peripheral nerve injury. It is a consequence of the pathological functioning of the nervous system rather than only a symptom. In fact, pain is a significant social, health, and economic burden worldwide. Flavonoids are plant derivative compounds easily found in several fruits and vegetables and consumed in the daily food intake. Flavonoids vary in terms of classes, and while structurally unique, they share a basic structure formed by three rings, known as the flavan nucleus. Structural differences can be found in the pattern of substitution in one of these rings. The hydroxyl group (–OH) position in one of the rings determines the mechanisms of action of the flavonoids and reveals a complex multifunctional activity. Flavonoids have been widely used for their antioxidant, analgesic, and anti-inflammatory effects along with safe preclinical and clinical profiles. In this review, we discuss the preclinical and clinical evidence on the analgesic and anti-inflammatory proprieties of flavonoids. We also focus on how the development of formulations containing flavonoids, along with the understanding of their structure-activity relationship, can be harnessed to identify novel flavonoid-based therapies to treat pathological pain and inflammation.

Background and Purpose: Maresin 1 (MaR1) is a specialised pro‐resolving lipid mediator with anti‐inflammatory and analgesic activities. In this study, we addressed the modulation of peripheral and spinal cord cells by MaR1 in the context of inflammatory pain.Experimental Approach: Mice were treated with MaR1 before intraplantar injection of carrageenan or complete Freund's adjuvant (CFA). Mechanical hyperalgesia was assessed using the electronic von Frey and thermal hyperalgesia using a hot plate. Spinal cytokine production and NF‐κB activation were determined by ELISA and astrocytes and microglia activation by RT‐qPCR and immunofluorescence. CGRP release by dorsal root ganglia (DRG) neurons was determined by EIA. Neutrophil and macrophage recruitment were determined by immunofluorescence, flow cytometry, and colorimetric methods. Trpv1 and Nav1.8 expression and calcium imaging of DRG neurons were determined by RT‐qPCR and Fluo‐4AM respectively.Key Results: MaR1 reduced carrageenan‐ and CFA‐induced mechanical and thermal hyperalgesia and neutrophil and macrophage recruitment proximal to CGRP⁺ fibres in the paw skin. Moreover, MaR1 reduced NF‐κB activation, IL‐1β and TNF‐α production, and spinal cord glial cells activation. In the DRG, MaR1 reduced CFA‐induced Nav1.8 and Trpv1 mRNA expression and calcium influx and capsaicin‐induced release of CGRP by DRG neurons.Conclusions and Implications: MaR1 reduced DRG neurons activation and CGRP release explaining, at least in part, its analgesic and anti‐inflammatory effects. The enduring analgesic and anti‐inflammatory effects and also post‐treatment activity of MaR1 suggest that specialised pro‐resolving lipid mediators have potential as a new class of drugs for the treatment of inflammatory pain.