Effect Of Lateral Habenula On The Hyperalgesia Induced By Depression And Underlying Mechanism In Rats

The interrelation of depression and pain is increasingly coming under scrutiny.The LHb plays an important role in conveying limbic forebrain inputs to midbrain structures and it is involved in a wide range of functions related to these systems.Although the lateral habenula(LHb)is widely implicated in the pathogenesis of depression and pain,its role in the interaction of depression and pain remains unknown.Thus,the aim of the current study was to investigate activity changes in neurons of the LHb in rats with depression-pain comorbidity.Single extracellular firing recording,the electrolytic lesion of LHb,ethological and immunofluorescence methods were used to compare firing rates and c-Fos expression of the LHb neurons in normal and model rats.Following subcutaneous injection of formalin into the hind paw to simulate natural pain,we assessed pain behavior in rats previously subjected to the chronic,unpredictable mild stress procedure(CUMS,an experimental model of depression).Pain sensitivity in model rats of depression was increased over that of controls.These rats also showed a significant increase in the firing activity of LHb neurons compared with normal rats.Significantly,about 73%of the neurons with high discharge frequency in LHb of model rats were pain-activated neurons(PANs),and the firing rates of PANs were inhibited by intraperitoneal injection of a tricyclic antidepressant,clomipramine.The results of immunofluorescence showed that the percentage of c-Fos positive cells in LHb was significantly increased in rats receiving CUMS only,rats receiving pain stimulation only,and rats receiving both CUMS and pain stimulation,but especially the last stimulation.The interaction effect was inhibited by injection of clomipramine and there was no difference in the percentage of c-Fos positive cells in the LHb between CUMS-pain-clomipramine and normal rats.The pain sensitivity was significantly decreased and in the sucrose preference and forced swimming test,the depression behavior was obviously improved after the lesion of LHb in the CUMS-lesion group compared with the CUMS-sham group.These results suggest that hyperactivity of the LHb neurons is involved in depression-pain comorbidity.