Validation of Peripheral Neuromodulation Mechanisms of Icariin in Knee Osteoarthritis–Related Chronic Pain

Knee osteoarthritis (KOA) is a chronic degenerative joint disease-causing chronic pain and disability. Neuromodulation of subchondral bone affects KOA-related pain and involves dorsal root ganglion (DRG). Our previous studies have demonstrated efficacy of icariin (ICA) in treating KOA, but neuromodulation mechanisms in peripheral nerves associated with the treatment of chronic pain in KOA remain unclear. This study aimed to investigate peripheral neuromodulation mechanisms of ICA in KOA-related chronic pain: (1) assessing therapeutic effect of ICA in a rat model of KOA-induced chronic pain; (2) investigating changes in pain-related nerve fibres and transient receptor potential vanilloid Subfamily 1 (TRPV1) pathway in subchondral bone following ICA treatment; and (3) exploring expression of pain-related Nogo-A/TRPV1 pathway in DRG, thereby elucidating neurotransmission of pain. Experimental results confirmed the curative effect of ICA on KOA by relieving chronic pain and pathological changes. ICA also effectively reduced bone remodelling, the area of pain-related positive nerve fibres and expression of TRPV1 in subchondral bone. Furthermore, ICA downregulated pain-related Nogo-A/TRPV1 pathway in the DRG. These findings provide new mechanistic insights into the therapeutic potential of ICA in relieving peripheral nervous system-related chronic pain in KOA.