Studying The Effects And Mechanisms Of Chronic Stress On The Postoperative Pain Transition In Mice

Background Chronic postsurgical pain that has developed after a surgical procedure,of at least 2 months duration and for which other causes(for examplechronic infection,continuing or recurring malignancy or a continuation of a pre-existing problem)have been excluded.Nowadays,theories for studying the development of chronic pain has been transferred from a biomedical model to a bio-psychosocial one.About ten to fifity percent patients can develope CPSP,which not only influences the patients’ quality of life after operations but also brings a heavy burden to our society,economy and medicine.As a whole,CPSP has being an important medical issue.As a pattern recognition receptor of the innate immune system,Toll like receptor 4 belongs to a part of interleukin 1/Toll like receptor superfamily.TLR4 consists of homologous structure domain of Toll/ IL-1 receptors and domain which is rich in leucine repeated sequences.Widely distributing in the body,in central nervous system,TLR4 mainly expresses in glia cells,predominately in microglia cells.What’s more,TLR4 can recognize a plenty of endogenous and exogenous associated molecular patterns and play a crucial role in the development of numerous infectious and noninfectious diseases.With the development of social economy and modern life pace speeding up,a lot of people have been in tremendous pressure for a long time in terms of a number of factors such as life,work,economy and human communications,among which social psychological factors have been paid more and more attentions to the influence on CPSP.Consequently,we conduct an experiment in mice through the establishment of social psychological stress model and incision pain model.The aim of the experiment can be elaborated as following: Firstly,we investigate the effects of chronic stress on emotions.Secondly,we observe how chronic stress influence the postsurgical pain and its recovery.Last but not the least,the underlying mechanisms would be studied.Method Forty-eight male C57BL/6 mice are randomly divided into 4 groups(n =12 for each group): nonstress+sham operative group,nonstress+operative group,chronic stress+sham operative group,chronic stress+operative group.Chronic restraint stress is applied to establish the chronic stress model.The mice are individually restrained for 8 h per day.This daily restraint is repeated for 10 consecutive days.Mice of operative group are received a left plantar incision to get a incision pain model.Body weight of each mouse is measured before and after chronic restraint stress,open field test,elevated plus maze test and forced swimming test were used to assess the anxiety and depression effects of chronic restraint stress on mice.All mice of each group undergo mechanical pain behavioral test at the first day before and1 th,3th,5th,7th,10 th,14th,18 th,21th,25 th,and 28 th days after incision.In terms of the molecular mechanisms,TLR4 expression is measured in lumbar spinal cord and hippocampus at the third and seventh day.Result In chronic stress group,the average body weight of the group decreases significantly when compared with the nonstress group(stress(-0.90±3.36)%vs nonstress(6.98±2.01)%;P < 0.01),total immobility time in the forced swim test significantly elevates(stress(148.5±7.2)s vs nonstress(128.3±4.1)s;P < 0.05)and the open arm duration declines significantly in the elevated plus maze test(stress(27.99±2.44)% vs nonstress(40.77±4.65)%;P < 0.05).There is no difference in velocity and total distance of the open field test.Further more,there is also no significant difference in mechanical pain threshold of baseline among the different groups(P > 0.05).The pain thresholds in chronic stress group and nonstress group go back to the baseline at the seventh day and the twenty-first day respectively.What’s more,in the3 th,5th,7th,10 th,14th,18 th days,the pain thresholds of chronic stress group decrease when compared with the nonstress group(P < 0.05 at the each time point).Chronic stress itself can not enhance the expression of TLR4 in spinal cord,and the plantar incision only can not increase the TLR4 expression in spinal cord either.Dramatically,TLR4 expression in spinal cord increases significantly at the third and seventh day after incision while other groups have no differences.When it comes to the hippocampus,we can find an increasing tendency of TLR4 expression of chronic stress +incision group at the third and seventh day after incision,but there are no differences between each group.Conclusion The chronic restraint model is well established and can simulate the daily psychosocial stress through ten days and eight hours per day restraint.The chronic stress can not only inhibits the mice body weights,but also induce certain behaviors such as anxiety and depression.In addition,chronic stress can also trigger hyperalgesia and make the acute postsurgical pain translate to CPSP,which may be attribute to the activation of TLR4 in lumbar spinal cord.