| Background:Postoperative pain is the main cause of distress after sugeries in most patients.There are 39%-50%of patients who have undergone surgeries suffering from postoperative pain,which not only increases the risks of postoperative complications but also is not conducive to postoperative recovery and prolongs hospital stay.Currently,opioids that are potent analgesics are a kind of the commonly used drugs for postoperative pain.However,opioids have many side effects at the dose of analgesic.Therefore,seeking for new and effective treatments for postoperative pain has become a crucial issue in clinical pratice.Esmolol,a selective?1-adrenoreceptor antagonist,is one of the most widely used agents for the treatment of cardiovascular-related diseases in the clinic.At the same time,studies have shown that esmolol has obvious effects in both intraoperative and postoperative analgesia.Esmolol was used in intraoperative and postoperative periods to reduce postoperative opioids and NSAIDs requirements in human patients.Both serotonin?5-HT?and 5-HT2B receptors are involved in the regulation of pain.However,the roles of 5-HT and 5-HT2B receptors in postoperative incisional pain are still unclear.Thus,we aimed to study the effect of intrathecal injection?IT?of esmolol on the postoperative pain model and to explore whether its analgesic mechanism is associated with5-HT and 5-HT2BB receptors.Methods and Results:Part One The role of intrathecal?IT?injection of esmolol in incisional pain Methods:Experiment 1:The rats?n=24?were randomly divided into three groups:sham group,surgery group and esmolol group.All the rats in the three groups underwent intrathecal catheterization surgeries.The rats in the surgery group and esmolol group took plantar incision surgeries on the sixth day after intrathecal catheterization surgeries.On the senventh day,esmolol was intrathecal injected in the rats of esmolol group.Respectively,equal amounts of normal saline were intrathecal injected in the rats of sham and surgery groups.The PMWTs of rats in three groups were measured before planar insicion,60min before drug administration and 5min,10min,15min,30min,60min after drug administration.Experiment 2:The rats?n=16?were randomly divided into two groups:sham group and esmolol group.The rats in the two groups underwent intrathecal catheterization surgeries.On the senventh day,esmolol and normal saline were respectively intrathecal injected in the rats of esmolol group and sham group.The changes of heart rate and blood pressure in the two groups were observed before drug administration,5 min,10 min,15min,20 min,25 min and 30 min after drug administration.Results:Experiment 1:There were no significant differences among three groups before planar incision?P>0.05?.One day after the establishment of the incisional pain model,the PMWTs of rats in the surgery group were obviously decreased compared with the sham group?P<0.001?and this finding indicates that the models of incision pain were successfully established.The PMWTs of rats in the esmolol group were significiantly increased at 5min?P<0.001?and 10 min?P<0.05?after intrathecal injection of esmolol compared with that in the surgery group as well as reached a maximum value at 5min after esmolol administration.This indicates that intrathecal injection of esmolol can relieve postoperative incision pain,but this effect is short-lived.Experiment 2:There were no significant statistical differences in HR and MAP between sham group and esmolol group?P>0.05?.Part Two 5-HT and 5-HT2B receptor mediate the analgesic effect of esmolol onincision-related pain in ratsExperiment 1:The role of 5-HT2BB receptor in incisional painMethods:The rats?n=24?were randomly divided into three groups:sham group,surgery group and RS127445 group.All the rats in the three groups underwent intrathecal catheterization surgeries.The rats in the surgery group and RS127445 group took plantar incision surgeries on the sixth day after intrathecal catheterization surgery.On the senventh day,RS127445 was intrathecal injected in the rats of RS127445 group.Respectively,equal amounts of normal saline were intrathecal injected in the rats of sham and surgery groups.The PMWTs of rats in three groups were measured before planar insicion,60min before drug administration and 60min,120min after drug administration.After the test was completed,the spinal cord tissues were isolated and the expression of 5-HT2B receptor was detected by Western blot.Results:There were no significant differences among three groups before planar incision?P>0.05?.One day after the establishment of the incisional pain model,the PMWTs of rats in the surgery group were obviously decreased compared with the sham group?P<0.001?and this finding indicates that the model of incision pain was successfully established.The PMWTs of rats in the RS127445 group were significiantly increased at 60min?P<0.001?after intrathecal injection of esmolol compared with that in the surgery group.This indicates that intrathecal injection of RS127445(5-HT2BB receptor antagonist)can relieve postoperative incision pain.The results of Western blot showed that the expression of 5-HT2B receptor was increased in surgery group compared with sham group?P<0.05?,and the expression of 5-HT2B receptor was decreased in the RS127445 group compared with surgery group?P<0.05?.Experiment 2:The effect of intrathecal injection of esmolol on 5-HT and 5-HT2B receptorin the spinal cord of incision-related pain behavior of ratsMethods:The rats?n=24?were randomly divided into three groups:sham group,surgery group and esmolol group.All the rats in the three groups underwent intrathecal catheterization surgeries.The rats in the surgery group and esmolol group took plantar incision surgeries on the sixth day after intrathecal catheterization surgeries.On the senventh day,esmolol was intrathecal injected in the rats of esmolol group.Respectively,equal amounts of normal saline were intrathecal injected in the rats of sham and surgery groups.The spinal cord tissues were isolated at 5 min after intrathecal inject of esmolol or normal saline and the expressions of 5-HT and 5-HT2B receptor were detected by ELISA?Western blot and IHC.Results:The results of ELISA showed that the content of 5-HT was increased in surgery group compared with sham group?P<0.05?,and the content of 5-HT was decreased in the esmolol group compared with surgery group?P<0.001?.The results of Western blot showed that the expression of 5-HT2B receptor was increased in surgery group compared with sham group?P<0.001?,and the expression of 5-HT2B receptor was decreased in the esmolol group compared with surgery group?P<0.001?.The results of IHC showed that the expression of 5-HT2B receptor was increased in surgery group compared with sham group,and the expression of 5-HT2B receptor was decreased in the esmolol group compared with surgery group.Main findings?1?Intrathecal administration of esmolol produced antinociceptive effects as well as MAP and HR were not influenced significantly by intrathecal administration of an analgesic dose of esmolol.?2?The antinociceptive effects were detected only at 5min and 10min and reached a maximum at 5min after intrathecal injection of esmolol.?3?5-HT2B receptor plays a role on mediating pain in the spinal cord.?4?Plantar incision would induce 5-HT release and increase the expression of 5-HT2B receptor in the spinal cord.?5?The expressions of 5-HT and 5-HT2B receptor in the spinal cord were down-regulated after intrathecal injection of esmolol.Main conclusionsIntrathecal injection of esmolol can produce analgesic effect,which may be related to inhibition of 5-HT release and the expression of 5-HT2B receptor in the spinal cord. |
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