The Function And Mechanism Of The Retina-vLGN/IGL Pathway In The Regulation Of Pain By Bright Light

Objective:Based on animal experiments,this study aims to further explore the precise circuit that mediates the antinociceptive effects of bright light,so as to provide an important theoretical basis for the application of light treatment.Methods:（1）First,acute inflammatory pain model induced by formalin and neuropathic pain model induced by chronic constriction injury（CCI）are introduced.Formalin test,von Frey test and hot plate test are used to explore the antinociceptive effects of bright light on different types of pain.（2）Then,we search for a pain-related light information transmission neural pathway,and use chemogenetics to explore the role of this neural pathway in the regulation of pain by bright light.At the same time,the effects of short-term and long-term bright light exposure on the activity of ventral lateral geniculate nucleus and intergeniculate leaflet（vLGN/IGL）neurons are investigated by immunocytochemistry staining and physiological recording.Results:（1）For wild-type mice,short-term light exposure increased the paw withdrawal latency in wild-type mice in a light-intensity-dependent manner(F_4,50=4.261,P=0.005).Meanwhile,Dunnett’s multiple comparison results showed that at least 3000 lux bright light was required to significantly elevate pain threshold（q=2.851,P=0.022）.For pain model,short-term bright light exposure significantly reduced the duration of licking in formalin model during the inflammatory phase（t=2.361,P=0.033）;long-term bright light exposure decreased hyperalgesia in CCI model in a time-dependent manner,1 week of bright light exposure was sufficient to elevate thermal pain threshold（t=2.489,P=0.024）,but at least 3 weeks of bright light exposure was required to attenuate mechanical sensitivity（t=2.870,P=0.011）.（2）Short-term bright light evoked c-Fos expression in vLGN/IGL（t=10.070,P<0.001）;both1-week bright light exposure（q=13.060,P<0.001）and 2-week bright light exposure（q=12.800,P<0.001）significantly increased the excitability of vLGN/IGL neurons.（3）Specific activation of vLGN/IGL-projecting retinal ganglion cells（RGCs）increased paw withdrawal latency in wild-type mice（t=2.300,P=0.040）,reduced the duration of licking in formalin model during both acute phase（t=3.251,P=0.004）and inflammatory phase（t=6.082,P<0.001）,and attenuated thermal sensitivity（t=2.918,P=0.014）and mechanical sensitivity（t=2.407,P=0.035）in CCI model.（4）Specific inhibition of vLGN/IGL-projecting RGCs suppressed the antinociceptive effects of bright light in formalin model（t=3.324,P=0.004）.Conclusions:（1）Bright light not only elevates pain threshold in wild-type mice,but also alleviates symptoms in both inflammatory pain and neuropathic pain models.（2）In terms of its mechanism,partial light-responsive RGCs in the retina can directly project to vLGN/IGL and can regulate pain by increasing the excitability of vLGN/IGL neurons.（3）Specific activation of vLGN/IGL-projecting RGCs suppresses nociception in both wild-type mice and pain models,while specific inhibition of RGCs-vLGN/IGL pathway significantly abolishes the antinociceptive effects of bright light.Taken together,we demonstrate the critical role of the RGCs-vLGN/IGL pathway in the antinociceptive effects of bright light.These findings enhance our understanding of the mechanism of the antinociceptive effects of bright light,highlight the important role of vLGN/IGL-related neural pathways in the formation and regulation of non-imaging-forming functions of light,and are expected to provide a theoretical basis for the promotion and application of light treatment as a new analgesia strategy.