| Chronic Inflammatory Pain is one of the most common chronic pain diseases in pain department.With the aging of the population,lack of regular exercise,long-term desk work and other factors,the incidence of inflammatory pain is increasing year by year.The disease is persistent and difficult to heal,with repeated symptom.Furthermore,it may even lead to a certain disability.To some extent,this kind of disease brings a serious economic burden to the patient’s family and society.If not treated in time,inflammatory pain may even cause central sensitization such as hyperalgesia or hyperalgesia,which is more difficult to treat.With the continuous advancement of medical methods and the rapid development of pain medicine,the minimally invasive treatment methods for inflammatory pain have become more and more abundant,but the treatment costs are not affordable for all families.Medication is the mainstay of treatment for inflammatory pain.However,there are many kinds of traditional non-steroidal anti-inflammatory drugs,and the gastrointestinal reactions are obvious,and cases of gastric ulcer and gastric bleeding caused by them are also reported from time to time.Although novel selective cyclooxygenase 2(COM-2)inhibitors can effectively reduce gastrointestinal reactions,they may also lead to cardiovascular diseases.The advantages of traditional Chinese medicine in the treatment of such diseases become more obvious.Although there is no disease name of inflammatory pain in traditional medicine,it can be judged that it belongs to the category of arthralgia in traditional Chinese medicine based on the clinical symptoms at the time of onset.According to ancient medical records and clinical experience in medicine,it is found that Tiannanxing-Shengjiang medicine has a more precise therapeutic effect in the treatment of inflammatory pain.However,due to the multi-component and multi-target characteristics of traditional Chinese medicine,there are few basic experiments on the treatment of chronic pain with Tiannanxing-Shengjiang,and there is no relevant research report on the main components and signaling pathways that play a role.As an emerging discipline,network pharmacology can draw a network diagram of"component-target-disease" through the method of overall system science,and describe the role of multi-component and multi-target in drug treatment of diseases,which is similar to the traditional Chinese medicine treatment.Therefore,in this study,the clinical reliability of traditional Chinese medicine in the treatment of inflammatory pain diseases was first judged by the method of Meta analysis,and then the main components and possible signaling pathways of Tiannanxing-Shengjiang medicine in the treatment of pain were analyzed by the method of network pharmacology.Scientific experiments preliminarily verified the efficacy of the drug on anti-inflammatory and analgesic.This study provides a reliable basis for giving play to the advantages of traditional Chinese medicine in the treatment of inflammatory pain,expands the choice of drugs in the treatment of diseases in pain departments,and provides a new theoretical method for the treatment of pain with integrated Chinese and Western medicine.Part 1 Meta-analysis of the efficacy and safety of traditional Chinese medicine in the treatment of chronic inflammatory painObjective:To investigate the efficacy and safety of traditional Chinese medicine in the treatment of chronic inflammatory pain.Methods:Computer retrieval Pubmed,Embase,Cochrane Library,Chinese Journal Full-text Database(CNKI),Wanfang,Chinese Scientific and Technological Periodicals Database(VIP),computer retrieval China Biomedical Literature Database(CBM)and other databases on the treatment of arthritis and tendon with traditional Chinese medicine.Randomized controlled trials(RCTs)for meningitis pain,the methodological quality of the literatures that met the inclusion criteria was evaluated using the quality evaluation tools recommended by the Cochrane Evaluation Manual,and the general information,treatment methods and efficacy of patients were extracted,and the above data were analyzed using STATA 15.1.analysis.Results:A total of 11 RCTs with a total of 1018 patients were included.Meta-analysis showed that compared with the control group,the pain VAS score of the experimental group was significantly decreased[WMD=-1.07(95%CI:-1.23～-0.91,P=0.000)];the inflammatory factor IL-1β was decreased[WMD=-6.49(95%CI:-10.40～-2.58,P=0.000)],IL-6 decreased[WMD=-3.11(95%CI:-5.12～-1.10,P=0.002)],MMP-3 decreased[WMD=-33.18(95%CI:-58.95～-7.41,P=0.000)],TNF-α decreased[WMD=-9.00(95%CI:-11.50～-6.49,P=0.000)],CRP decreased[WMD=-2.1 6(95%CI:-2.75～-1.57,P=0.000)];there was no significant difference in the incidence of adverse reactions[RR=2.30(95%CI:0.11-50.21,P=0.597)].Conclusion:Compared with simple western medicine,traditional Chinese medicine can significantly improve the clinical efficacy of patients in the treatment of inflammatory pain without increasing the incidence of adverse reactions.Part 2 study on anti-inflammatory and analgesic effect of Tiannanxing-Shengjiang drug pairObjective:To investigate the anti-inflammatory and analgesic activity of Tiannanxing-Shengjiang drug pair.Methods:The anti-inflammatory effect of different doses of Tiannanxing-Shengjiang was observed by carrageenan-induced rat paws edema on SD rats and xylene-induced ear edema on ICR mice,while its analgesic activity was evaluated by acetic acid-induced writhing test on ICR mice and hot-plate test.Results:In the anti-inflammatory test,the high-dose group of Tiannanxing-Shengjiang could significantly inhibit the edema on rats’ paws caused by carrageenan in the first 2 hours(P<0.01),while the effect of medium and low dose groups was not significant.In the experiment of xylene-induced ear edema on ICR mice,the high-dose group of Tiannanxing-Shengjiang could significantly inhibit the ear edema of mice(P<0.01),while the medium and low dose groups could also effectively inhibit the thickness of ear edema of mice(P<0.05).In the writhing test,the high-dose group of Tiannanxing-Shengjiang could significantly reduce the writhing times induced by intraperitoneal injection of acetic acid in mice(P<0.01),and the medium and low-dose groups could also play a good effect(P<0.05),while in the hot-plate test,Tiannanxing-Shengjiang had only a slight effect on the pain threshold of hot-plate in mice,which was not statistically significant.Conclusion:Tiannanxing-Shengjiang drug pair has a good anti-inflammatory effect,while its peripheral analgesic effect is strong but central analgesic effect is not obvious,and there is a certain dose-response relationship.Part 3 a network pharmacology and molecular docking-based method for mechanistic investigation of Tiannanxing-Shengjiang drug pair acting on pain diseaseObjective:To analyze the potential targets and mechanisms of action of Tiannanxing-Shengjiang drug pair for the treatment of pain using a network pharmacology approach.Methods:The TCMSP database was used to screen the active components and targets of the drug pair"Tiannanxing-Shengjiang”,and target prediction was performed by SwissTarget and other databases for unclear targets those TCMSP database didn’t give.The target genes related to pain were retrieved from the DisGeNet database,and the intersection targets were obtained by mapping the active ingredient targets and pain-related genes together by the Venn diagram.Cytoscape 3.7.2 software was used to construct the component-target-disease network diagram.Protein-Protein Interaction(PPI)network was constructed and analyzed by String database to screen out the important targets.GO enrichment analysis and KEGG pathway enrichment analysis of intersection targets were performed through the DAVID website.Docking validation of major active ingredients and targets was performed using autodocktoolsResults:A total of 10 active ingredients were screened from Tiannanxing-Shengjiang drug pair and we found 63 intersection targets between drug and disease,including CNR1,ESR1,MAPK3,CYP3A4,JUN,HDAC1,etc.The biological processes derived from GO analysis included inflammatory response,positive regulation of EKR1 and EKR2 cascade,positive regulation of transcription from RNA polymerase II promoter,G-protein coupled receptor signaling pathway,etc.A total of 53 pathways were obtained from KEGG,among which those more closely related to pain included calcium signaling pathway,cholinergic synapse,estrogen signaling pathway,cancer pathway,and serotonergic synapse.The results of 35 molecular docking showed that most of them had superior docking activity,Dihydrocapsaicin and stigmasterol had the best binding situation to the core target proteins,and the targets such as CNR1 and mapk3 were the target proteins with the best binding activity to the key chemical components in drug pairs.Conclusion:The active ingredients such as Stigmasterol,β-sitosterol and dihydrocapsaicin in the Tiannanxing-Shengjiang pair may act on various types of pain by acting on CNR1,ESR1,MAPK3,CYP3A4,JUN,HDAC1 and other targets to regulate intracellular calcium ion conduction,cholinergic prominent signaling,cancer signaling pathway,etc.,providing a theoretical basis for further experimental design.Theoretical basis for further experimental design.Part 4 preliminary investigation on the analgesic effect of Tiannanxing-Shengjiang on model of inflammatory pain by targeting ERK signalingObjective:To investigate changes in ERK(and p-ERK)and cannabinoid receptor 1 expression in the spinal dorsal horn and dorsal root ganglia in a complete Freund’s adjuvant induced rat plantar inflammation model and changes in mechanical pain thresholds.Methods:A total of 60 healthy male SD rats of SPF grade were randomly divided into four groups:control group,model group,Tiannanxing-Shengjiang group and ERK inhibitor(U0126)groups,with 15 rats in each group.Tiannanxing-Shengjiang group was intragastrically administered with 9 g/kg/d TCM,while the control and model groups were intragastrically administered with equal volume of normal saline,and ERK inhibitor group received daily intraspinal injection of 10 μL of U0126.The 50%mechanical pain paw withdrawal threshold(50%MWT)values of all rats before,1,3,and 7 days after modeling were measured,and the right hind foot,spinal cord,dorsal root ganglia,and serum of rats were collected at the corresponding time points.ERK and p-ERK levels in the spinal dorsal horn and DRG of rats at each time point were determined by Western blot analysis.Cannabinoid receptor 1,ERK,and p-ERK levels in the spinal dorsal horn were determined by immunohistochemistry.ELISA was used to measure TNF-α、IL-6 and IL-1 β in rat paw tissue and serum at each time point.Results:Compared with the model group,there was no significant difference in mechanical pain threshold value of rats in the TCM group on the 1st day of modeling,but it significantly decreased on the 3rd and 7th days(P<0.05).The expressions of ERK and p-ERK in the spinal dorsal horn and dorsal root ganglia of rats in the TCM group and ERK inhibitor group were decreased compared with those in the model group on days 1,3,and 7 after modeling(P<0.05).ELISA results showed that IL-6,IL-1 β and TNF-α amounts were all significantly decreased(P<0.05).The immunohistochemical results suggested that the expression of CNR1 in the spinal dorsal horn of rats in the TCM group was significantly increased on days 3 and 7 after modeling(P>0.05). |
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