Targeting the oxidative stress-neuroinflammation axis: the mechanism of arctigenin's broad-spectrum analgesia with limited side effects.

BACKGROUND: Arctigenin (AG), a natural lignan compound, has been reported to reveal its anti-inflammatory effects in glucose, lipid metabolism and type 2 diabetes mellitus. An increasing number of studies suggest that microglia activation evoked neuroinflammation is known to contribute to the development and progression of neuropathic pain. This study aims to investigate the role and mechanism of AG in ameliorating spared nerve injury (SNI)-induced neuropathic pain.

MATERIALS AND METHODS: SNI model was defined as suffering severe hyperalgesia and allodynia and established in C57BL/6 male mice. The effects of AG on SNI mice and its underlying mechanisms were examined by behavioral tests, qPCR, western blotting, ELISA, immunofluorescence (IF), ROS test, transmission electron microscopy and mitochondrial test.

RESULTS: We found that intraperitoneal administration of AG produced pronounced dose-dependent antinociceptive effects in SNI mice. Moreover, AG treatment significantly inhibited ERK, JNK and p38 phosphorylation in the lumbar spinal cord of SNI mice, but not AMPK, PGC-α and mTOR pathway. Meanwhile, we found that pretreatment with the U0126 or SB203580 or SP600125, 30 min prior to AG administration, blocked the analgesic effects of AG in SNI mice. Furthermore, mechanistic studies indicated that at the spinal cord level, AG produced pain relief through restoring mitochondrial biogenesis, inhibiting oxidative damage, suppressing microglia and astrocyte activation and decreasing the production of pro-inflammatory factors, which direct contributed to neuronal modulation. pretreating with minocycline reduced but did not completely block the analgesic effect of AG, indicating that the activation of spinal cord microglia is not necessary for the antiallodynic effect of AG. In addition to neuropathic pain, AG exhibits significant analgesic effects across diverse models, indicating its broad-spectrum analgesic properties. Concurrently, studies on short-term toxic side effects revealed that prolonged AG injection had no impact on hepatic or renal functions and produced none of the typical analgesic side effects, including tolerance, addiction, or constipation, indicating limited antinociceptive side effect.

CONCLUSIONS: The present study is the first to provide evidences that AG may represent a novel therapeutic target with high analgesic activity and low side effects for the treatment of neuropathic pain.