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40 Hz light flickering alleviates chronic pain via adenosine signaling in the retina-amygdala pathway

Jiawang Chen^1,2,† , Tao Xu^1,2,† , Chenchen Zhang^3,4 , Li Li^5,6,7 , Yan He¹ , Zhaoxia Sun^3,4 , Jiasheng He¹ , Zhimo Yao¹ , Peng Cai^3,4 , Yipeng Huang^3,4 , Fenfen Ye¹ , Wei Guo¹ , Manli Jia¹ , Jia Qu^1,2,* , Jiang-Fan Chen^1,2,* , Yi Zhang^1,2,3,4,*

¹The Eye and Brain Center, State Key Laboratory of Eye Health, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
²Oujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Wenzhou, Zhejiang, China
³Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
⁴Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China
⁵Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Wenzhou, Zhejiang, China
⁶Key Laboratory of Precision Anesthesiology of Zhejiang Province, Department of Anesthesiology, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
⁷Wenzhou Municipal Key Laboratory of Neurodevelopmental Pathology and Physiology, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
^†These authors contributed equally: Jiawang Chen, Tao Xu
* Correspondence: Jia Qu(qujia@eye.ac.cn)Jiang-Fan Chen(chenjf555@gmail.com)Yi Zhang(yizhang@wmu.edu.cn)

Chronic pain affects over 20% of the global population, yet frontline treatments remain limited in efficacy and are often hampered by serious side effects. In search of novel and effective neuromodulation alternatives, we discovered that 40 Hz flickering light effectively alleviates inflammatory and neuropathic pain in mice. We identified the retina-central amygdala (CeA) pathway as a critical conduit for the analgesic effects of 40 Hz flickering light. Using circuit-specific manipulations, we demonstrated that activation of the retina-CeA pathway is both sufficient to mimic and necessary to mediate the analgesic outcomes of 40 Hz light stimulation. In terms of mechanism, we found that 40 Hz light flickering significantly increases extracellular adenosine levels in the CeA. Local pharmacological blockade of equilibrative nucleoside transporters prevented this adenosine increase and abolished the analgesic effects of 40 Hz light flickering, whereas focal adenosine infusion phenocopied the light-induced analgesia. Both interventions required A2A receptor signaling to suppress nociceptive responses. Furthermore, we found that hyperalgesia could be destabilized in the CeA and reversed by 40 Hz light stimulation or adenosine infusion, mirroring memory reconsolidation processes and implicating the CeA as a key locus for pain memory erasure. Collectively, our findings demonstrate the multifaceted therapeutic benefits of 40 Hz light flickering as a novel non-invasive approach for pain management and reveal a distinct retina-CeA circuit and adenosine signaling mechanism for control of chronic pain and pain memory.

https://doi.org/10.1038/s41422-026-01227-7

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