The Mechanism Of 5-HT Descending Pathway In Decreased Pain Threshold Caused By Nicotine Withdrawal

It is well known that smoking is still popular in our country,approximately 316 million chinese adults are current smokers,and more than 724 million non-smokers are exposed to second-hand smoke.Long-term smoking can lead to nicotine dependence.Cigarette smoking leads to cancer,respiratory disease,and cardiovascular disease,and is responsible for 1 million deaths annually in China.With the development of medical technology,patients who need surgery and general anesthesia has significantly increased,and most of them required to stop smoking before surgery.Smoking is associated with pain.The association between nicotine withdrawal and postoperative pain is a concern of anesthesiology research.Nicotine markedly stimulates the central nervous system(CNS)and at low doses produces analgesia.The antinociceptive eff ects of nicotine have been proven in experimental pain studies with both animal models and human models.This mechanism still is not fully understood.Nicotine withdrawal in nicotine-dependent patients appears to result in hyperalgesia or lower pain threshold after surgical procedures.Studies using electric shocks or exposure to freezing water indicated that nicotine-deprived smokers had a lower pain threshold than did smokers.In our previous clinical work,we enrolled 148 male patients(68 non-smokers and 80 smokers)who underwent hepatic resection and received postoperative patient-controlled intravenous analgesia.Patients were tested for preoperative pain thresholds in response to electrical stimuli,and we recorded the cumulative amount of extra morphine equivalent required after surgery.It turned out that compared to non-smokers,nicotine-abstinent patients exhibited lower pain thresholds before surgery and demanded a greater amount of extra morphine equivalent after surgery.Abstinent smokers also exhibited more severe postoperative pain relative to non-smokers.Why nicotine withdrawal would lead to lower threshold? Currently,the mechanism still is not fully understood.The nucleus raphe magnus(NRM)is located in the central part of the rostral ventral medial area and is closely related to the modulation of pain perception.More importantly,TPH immunoreactive neurons were mainly distributed in NRM,while 5-HT is an important neurotransmitter in the endogenous descending pain regulation system.Our previous work has proved that the 5-HT content in CSF of nicotine withdrawal animal model is significantly reduced.Besides,we found that there was a significant neuronal loss in NRM in a rat model of nicotine withdrawal.The purpose of this study was to explore the relationship between nicotine withdrawal,pain threshold,NRM neuronal loss and 5-HT level in the CNS.The research methods include:1.To investigate the effect of smoking cessation on pain threshold during the perioperative period in patients undergoing hepatic resection.2.To observe the changes in mechanical withdrawal threshold(MWT)and thermal withdrawal latency(TWL)in a rat model of nicotine withdrawal.3.To examine the effects of nicotine withdrawal on the number of neurons in the nucleus raphe magnus(NRM)and the expression of TPH positive neurons in NRM.And determine the 5-HT levels in cerebrospinal fluid in a rat model of nicotine withdrawal.4.To explore the effect of 5-HT signaling pathway on pain threshold in nicotine withdrawal rats,we up-regulation and down-regulation of 5-HT signaling pathway.Results:1.Smokers deprived of cigarettes exhibited decreased pain thresholds before surgery and required a higher quantity of postoperative extra morphine equivalent than non-smokers.2.Not only the mechanical and thermal pain threshold but also the 5-HT levels in CSF were significantly decreased.3.We found that the number of NRM neurons and serotonergic(5-HT)neurons in NRM were decreased in rats with nicotine withdrawal.4.Administration of 5-HT or TPH overexpression virus significantly increased the loss of neurons,and the thermal hypersensitivity induced by nicotine withdrawal.We conclude that nicotine withdrawal induces death of NRM neurons that can be reduced or abolished 5-HT or TPH overexpression virus.We propose that the loss of NRM neurons shifts the balance of descending control from pain inhibition to pain facilitation.