The Role Of Lateral Habenula-rostromedial Tegmental Nucleus Circuit In Regulation Of Pain In Mice

Pain affects people’s daily life seriously,and it’s often accompanied by negative emotions such as anxiety and depression.As an aversive center,lateral habenula(LHb)can be activated by negative emotions such as aversive stimulus and stress.Meanwhile,LHb is also an important pain regulator,it inhibits and facilitates pain perception by affecting the descending pain regulation system,but how LHb involved in pain pathways is not very clear.The rostromedial tegmental nucleus(RMTg)receives major LHb glutamatergic input,which is rich in GABAergic neurons.Activating RMTg GABAergic neurons induce a decrease in the pain threshold of mice(hyperalgesia).It also can emanate efferent to the brain areas,such as VTA or DRN,which is related to pain and rich in dopaminergic or serotonergic neurons.Both LHb and RMTg are related to pain,but whether the LHb-RMTg pathway is directly involved in the regulation of pain is unclear,and how the LHb-RMTg pathway transmit pain information remains to be further demonstrate.In this study,chemogenetic and optogenetic technology combined with behavior testing were used.Chemogenetic specifically activate or inhibit the LHb-RMTg pathway to detect mechanical pain and thermal pain changes in mice,the 50% paw withdrawal mechanical threshold(PWMT)was measured by the up-down method with Von Frey filament,the paw withdrawal thermal latency(PWTL)was measured by the Hargreaves method with the plantar thermal pain apparatus.In addition,we combined with the inflammatory pain model induced by complete Freund’s adjuvant(CFA)to demonstrate that the excitatory neurons in LHb projecting to RMTg are involved in pain regulation.In order to demonstrate the role of LHb glutamatergic neurons,i.e.the role of the LHb glutamatergic neurons-RMTg neural pathway in the regulation of pain,we used optogenetic technology to specifically inhibit of the Vglut2LHb-RMTg pathway to detect changes in pain in miceThe results showed that chemogenetic activation of the LHb-RMTg pathway induced thermal hyperalgesia in mice,but did not affect mechanical pain.CFA injection can induce hyperalgesia in mice,and PWMT and PWTL are both decreased,chemogenetic inhibition of the LHb-RMTg pathway significantly increased the PWTL and can restored the thermal hyperalgesia induced by CFA to the normal threshold.Consistent with the results of chemogenetic specifical inhibition,optogenetic inhibition of the Vglut2LHb-RMTg pathway in Vglut2-ires-cre mice induced thermal analgesia,which could alleviate CFA-induced thermal hyperalgesia in mice.In this study,we found that the LHb glutamatergic neuron-RMTg neural pathway is involved in the regulation of thermal pain,and inhibition of the LHb glutamatergic neuron-RMTg pathway reduced the response to thermal stimulation in mice and alleviated thermal hyperalgesia in pain caused by inflammation.