n-3 polyunsaturated fatty acids inhibit the IL-1β/SP positive feedback loop in intervertebral disc endplate and low back pain-related behaviors in mice.

Abstract

Cartilage endplate (CEP) degeneration is a primary cause of intervertebral disc degeneration (IVDD) and subsequent low back pain (LBP). While n-3 polyunsaturated fatty acids (PUFAs) have been confirmed to suppress inflammation and delay IVDD, their effects and molecular mechanisms on LBP remain unclear. This study utilized C57BL/6 wild-type (WT) and fatty acid transgenic-1 (fat-1) transgenic (TG) mice to establish aged mouse model and lumbar spine instability (LSI) models. Behavioral tests revealed pronounced LBP symptoms and accelerated CEP degeneration in WT-aged and WT LSI mice. Conversely, TG mice exhibited significantly improved hypersensitivity and attenuated CEP degeneration. The elevation of endogenous n-3 PUFA substantially suppressed the elevated expression of substance P (SP) in degenerative CEPs. In vitro, IL-1β and SP established a positive feedback loop of expression in chondrocytes. n-3 PUFAs inhibited IL-1β/SP expression and release by downregulating key receptors (IL-1R1, NMDAR, and NK1R), thereby disrupting the positive feedback loop associated with IL-1 and SP and improving the CEP inflammatory microenvironment. These findings shed light on the mechanism through which n-3 PUFAs alleviate LBP by modulating neuropeptide expression in chondrocytes.