| Background/ObjectiveOpioids,as a common analgesic,are often used to treat various clinical pains such as acute pain,complex neuralgia,and cancer pain.During the use of opioid drugs,it has been found that long-term repeated and high-dose use of this kind of drugs,especially for cancer patients,not only increases the side effects but also easily causes patients to have tolerance and dependence on it.Therefore,opioid tolerance and opioid addiction generally exist in cancer pain patients.Opioid tolerance means that after long-term use of opioid drugs,the dosage of opioid drugs needs to be increased to achieve the same analgesic effect.The analgesic effect produced by the original dosage gradually decreases or even disappears.Although there are many studies on opioid tolerance at present,the related mechanism is still unclear,and there is no effective treatment.Acupuncture has been used for clinical analgesia for thousands of years.In recent years,electroacupuncture has been found to effectively fight opioid addiction and relieve cancer pain.However,there are different opinions on the selection of acupuncture points in the treatment process,and the specific therapeutic mechanism of electroacupuncture to relieve opioid tolerance needs further study.This paper intends to explore the effectiveness of electroacupuncture at Neiguan and Zusanli points in relieving opioid tolerance and its related mechanism through clinical and basic research.Methods1.Clinical observation on electroacupuncture at Neiguan and Zusanli point to relieve opioid tolerance of cancer pain patients60 patients with cancer pain were randomly divided into electroacupuncture group and sham electroacupuncture group,with 30 cases in each group.Patients in both groups received oral opioid analgesic therapy,and the doses of all opioids were compared with converted morphine equivalents.In the EA group,EA was applied to stimulate bilateral PC 6 and ST 36,and the needle was retained for 30 minutes.In the sham EA group,sham EA was applied to stimulate bilateral PC 6 and non-acupoint points 15mm beside ST 36 and the needle was retained for 30 minutes.Patients in the two groups received treatment 14 times,once every other day.If explosive pain occurs during treatment,both groups of patients are treated with morphine injection.Both groups were treated with electroacupuncture for 14 times,once a day.The opioid tolerance index,NRS score before and after treatment,the number of burst pain,the duration of pain relief,the incidence of adverse reactions and quality of life assessment of the two groups were observed.2.Clinical observation on electroacupuncture at Neiguan point and Zusanli point to relieve acute tolerance and hyperalgesia of remifentanil80 patients undergoing elective thyroidectomy were randomly divided into electroacupuncture group and sham electroacupuncture group,40 cases in each group.Patients in both groups were treated with electroacupuncture in the ward 24 hours before operation,while those in electroacupuncture group were treated with electroacupuncture to stimulate bilateral Neiguan and Zusanli points,leaving acupuncture for 30 minutes.In the sham electroacupuncture group,sham electroacupuncture was used to stimulate bilateral Neiguan points and non-acupoint points 15mm away from Zusanli point,leaving acupuncture for 30 minutes.0.3μg/kg/min remifentanil was injected intravenously in both groups.EvF device was used to measure the threshold of mechanical pain around the skin incision and the non-dominant arm of the two groups of patients before operation,30 minutes after operation,6 hours after operation,24 hours after operation and 48 hours after operation.The incidence of hyperalgesia,pain score and adverse reactions of the two groups were recorded at each time point after operation.3.The effects of electroacupuncture in relieving morphine tolerance mediated by P2X3 receptor via ERK signaling pathwayForty healthy male SD rats,weighing 180～220g,were randomly divided into five groups(n=8):saline group(group S),morphine group(group M),morphine+sham electroacupuncture group(group M+SEA),morphine+electroacupuncture group(group M+EA)and morphine+A-317491 group(group M+A-317491).The morphine tolerance model in rats was established by subcutaneous injection of morphine.In group M+EA,electroacupuncture was started to stimulate bilateral Neiguan and Zusanli points of rats 30 minutes before morphine injection for 7 consecutive days.For group M+SEA,sham electroacupuncture was used to stimulate the non-acupoints 5mm apart from the bilateral Neiguan point and 5mm apart from Zusanli point.Rats in group M+A-317491 received intraperitoneal injection of A-317491 30 minutes before morphine injection.Normal saline group was injected with the same amount of normal saline at each time point.The mechanical pain threshold(MWT)and tail-flick Latency(TFL)were measured before the model preparation and on the 1st,3rd,5th and 7th day after the model preparation.On the 7th day after the model was established,the rats were killed,and the dorsal root ganglion of spinal cord was taken.The expression changes of P2X3 receptor protein,ERK and phosphorylated ERK in the dorsal root ganglion of spinal cord were measured by Western bolt method,and the expression changes of P2X3 receptor were observed by immunofluorescence.Results1.Clinical observation on electroacupuncture at Neiguan and Zusanli point to relieve opioid tolerance of cancer pain patientsCompared with sham electroacupuncture group,the opioid tolerance index of patients in electroacupuncture group was lower than that in sham electroacupuncture group,and the difference was statistically significant.After treatment,the NRS score of patients in electroacupuncture group was lower than that in sham electroacupuncture group,with fewer times of pain outbreak,longer duration of pain relief and higher quality of life score.In terms of adverse reactions,the incidence of nausea and vomiting in electroacupuncture group was lower than that in sham electroacupuncture group.2.Clinical observation on electroacupuncture at Neiguan point and Zusanli point to relieve acute tolerance and hyperalgesia of remifentanilThe mechanical pain threshold near the incision and forearm of patients in electroacupuncture group at 30 minutes,6 hours after operation was higher than that in sham electroacupuncture group,the same as the pain score.At 30 minutes,6 hours after operation,the incidence of postoperative hyperalgesia in sham electroacupuncture group was higher than that in electroacupuncture group.There was no significant difference in mechanical pain threshold,hyperalgesia rate and pain score between the two groups at 24 hours and 48 hours after operation.There was no significant difference in the incidence of adverse reactions between the two groups.3.The effects of electroacupuncture in relieving morphine tolerance mediated by P2X3 receptor via ERK signaling pathwayThe mechanical pain threshold and tail flick latency of rats in group M decreased from the 1st to 7th day after the model was established.The expression of P2X3 receptor protein and pERK in dorsal root ganglion were higher than that of group S.On the 5th and 7th day after morphine injection,compared with group M,the mechanical pain threshold and tail flick latency of rats in group M+EA and group M+A-317491 were higher,and the expression of P2X3 receptor and pERK were lower,the difference was statistically significant.There was no significant difference between group M+SEA and group M in mechanical pain threshold,tail flick latency,P2X3 receptor and pERK expression.Conclusions1.Electroacupuncture at Neiguan and Zusanli points may reduce the occurrence of opioid tolerance,relieve pain and improve the quality of life of cancer pain patients.2.Electroacupuncture at Neiguan and Zusanli points could reduce the incidence of acute tolerance and hyperalgesia after remifentanil infusion in patients undergoing thyroidectomy,and reduce postoperative incision pain with less adverse reactions.3.Electroacupuncture at Neiguan point and Zusanli point could effectively relieve morphine tolerance,and its mechanism may be related to inhibiting the expression of P2X3 receptor mediated by ERK signaling pathway. |
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