Light flickering with 40 Hz causes analgesia via activation of a retina-amygdala pathway and the local release of adenosine.

Abstract

In a recent article published in Cell Research, Chen et al. reported that light flickering at 40 Hz effectively counteracts chronic pain in Complete Freund Adjuvant (CFA)-treated mice and in mice whose tibial and common peroneal nerves were ligated (spared nerve injury, SNI) [1]. These mice served as models for inflammatory and neuropathic pain, respectively. After establishing that 40 Hz light flickering exerted analgesia in both pain models, a systematic search started for the neuronal pathways involved and the conditions required for this effect. The combination of retrograde and anterograde tracing techniques indicated that retinal ganglion cells (RGCs) project monosynaptically to the central amygdala (CeA), and chemogenetic or optogenetic activation of this pathway simulates the effects of 40 Hz light stimulation. Genetic sensors for adenosine expressed in the CeA proved that such a light stimulation caused an increase in the local concentration of adenosine, via the promotion of the equilibrative adenosine transporter-mediated outflow of the nucleoside from CNS cells. The enriched adenosine levels apparently stimulated A_2A receptors (Rs) as proved by the abolition of 40 Hz light flickering-induced analgesia by pharmacological blockade of A_2ARs, or their genetic knockdown/knockout. The target neurons in the CeA were identified as belonging to the proenkephalin-containing type; their selective ablation abolished the effect of light stimulation. Finally, two capsaicin injections, 3 h apart, the second one either combined with saline or the protein synthesis inhibitor anisomycin, showed that anisomycin deleted chronic pain memory traces. Hence, 40 Hz light flickering may be a non-pharmacological manipulation for alleviating chronic pain in humans, without the cardiovascular and CNS side effects inherent to systemic adenosine application.