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.

In the present study, the effect and mechanism of action of the flavonoid naringenin were evaluated in superoxide anion donor (KO₂)-induced inflammatory pain in mice. Naringenin reduced KO₂-induced overt-pain like behavior, mechanical hyperalgesia, and thermal hyperalgesia. The analgesic effect of naringenin depended on the activation of the NO−cGMP−PKG−ATP-sensitive potassium channel (K_ATP) signaling pathway. Naringenin also reduced KO₂-induced neutrophil recruitment (myeloperoxidase activity), tissue oxidative stress, and cytokine production. Furthermore, naringenin downregulated KO₂-induced mRNA expression of gp91phox, cyclooxygenase (COX)-2, and preproendothelin-1. Besides, naringenin upregulated KO₂-reduced nuclear factor (erythroid-derived 2)-like 2 (Nrf2) mRNA expression coupled with enhanced heme oxygenase (HO-1) mRNA expression. In conclusion, the present study demonstrates that the use of naringenin represents a potential therapeutic approach reducing superoxide anion-driven inflammatory pain. The antinociceptive, anti-inflammatory and antioxidant effects are mediated via activation of the NO−cGMP−PKG−K_ATP channel signaling involving the induction of Nrf2/HO-1 pathway.

Naringenin: an analgesic and anti-inflammatory citrus flavanone