Cordycepin ameliorates morphine tolerance by inhibiting spinal cord ferroptosis and inflammation via targeting SIRT1

Morphine tolerance, a significant clinical challenge arising from prolonged morphine use, is increasingly recognized to involve neuroinflammation. Currently, effective pharmacological agents specifically targeting neuroinflammation to counteract morphine tolerance in clinical settings are lacking. Cordycepin, the primary bioactive compound found in the fungus Cordyceps militaris, has demonstrated antioxidant and anti-inflammatory effects across various disease models.

In this study, we established a rat model of morphine tolerance to investigate the potential of cordycepin to impede the development of this tolerance and to elucidate the underlying mechanisms. Our findings revealed that cordycepin treatment effectively mitigated the development of morphine tolerance and attenuated mitochondrial damage associated with ferroptosis. This was evidenced by a reduction in the levels of reactive oxygen species, malondialdehyde, and ferrous iron, coupled with an increase in the levels of superoxide dismutase and glutathione.

Furthermore, cordycepin treatment decreased the secretion of pro-inflammatory cytokines, including interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha. Notably, cordycepin upregulated the expression of sirtuin 1, solute carrier family 7 member 11, and glutathione peroxidase 4. Subsequent investigations using EX-527, a selective inhibitor of sirtuin 1, demonstrated that it abolished the beneficial effects of cordycepin in morphine-tolerant rats.

These results collectively suggest that cordycepin can alleviate the development of morphine tolerance by inhibiting spinal cord ferroptosis and inflammation through the modulation of sirtuin 1. Thus, Thiomyristoyl our study highlights the protective properties of cordycepin and underscores its therapeutic potential as a pharmacological agent for the treatment and prevention of morphine tolerance.