补骨颗粒治疗骨关节炎慢性疼痛的机制研究
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摘要
目的:通过观察补骨颗粒对骨关节炎患者慢性疼痛及缓激肽(BK)、降钙素基因相关肽(CGRP)、转化受体电位阳离子通道亚家族A成员1(TRPA1)的影响,探讨补肾活血中药对骨关节炎慢性疼痛的影响机制,为临床防治骨关节炎慢性疼痛提供依据。方法:选取40例膝关节疼痛的骨科门诊患者,按照美国风湿病学会(ACR)标准诊断为单侧或双侧膝骨关节炎,中医诊断符合《中医病证诊断疗效标准》中骨痹(肾虚血瘀型),患者每日严格按时口服补骨颗粒,并在口服中药第0,7,14天时采用视觉模拟评分法(VAS)评估患者膝关节静息痛,同时抽取3～4 mL静脉血行TRPA1、CGRP及BK检测,所有检测值记录于预先设置好的表格内,使用SPSS 20.0软件进行统计分析。结果:共有32例患者按照试验方案服药,所纳入患者在口服中药前的静息痛VAS评分为54.38分,治疗7 d(44.69分)及14 d(32.81分)后患者的平均静息痛均明显缓解(F=44.323,P=0.000);治疗前患者BK值为7.72 ng·mL~(-1),治疗7 d后(6.61 ng·mL~(-1))与14 d后(5.98 ng·mL~(-1))均明显降低(F=30.025,P=0.000);治疗后CGRP下降,但多重比较发现,治疗前与治疗7,14 d比较,差异有统计学意义(P=0.015,P=0.002),而治疗7 d与14 d差异无统计学意义(P=0.469);治疗后TRPA1值下降,多重比较发现,治疗前与治疗7 d差异无统计学意义(P=0.243),治疗前与治疗14 d差异有统计学意义(P=0.000),治疗7 d与14 d差异有统计学意义(P=0.000)。结论:补骨颗粒能够有效缓解骨关节炎患者慢性疼痛,这可能通过抑制TRPA1、CGRP及BK的表达或分泌,从而起到抑制外周感受器敏化及中枢敏化的作用。
Objective:By observing the effects of Bugu Keli(补骨颗粒)on chronic pain,BK,CGRP and TRPA1 in patients with osteoarthritis,to explore the its mechanism,so as to provide evidence for clinical prevention and treatment.Methods:Forty patients with knee joint pain were recruited and diagnosed as unilateral or bilateral knee osteoarthritis according to the criteria of American Rheumatology Society.Then they were diagnosed as bone bi(of kidney deficiency and blood stasis type)in terms of The Criteria of Diagnosis and Curative Effect of Osteoarthritis.The patients were given Chinese medicine for tonifying kidney and activating blood circulation strictly and on time.Before taking medicine,the seventh day and the fourteenth day after that,VAS was used to assess the rest pain of knee joint.At the same time,3 ～ 4 mL venous blood samples were taken for TRPA1,CGRP and BK detection.All the detection values were recorded in the pre-set tables and statistically analyzed with software SPSS 20.0.Results:A total of 32 patients were treated with Chinese medicine.The VAS score of rest pain before oral administration was 54.38.The average resting pain of patients after 7 days(44.69 points)and 14 days(32.81 points)was significantly relieved(F = 44.323,P = 0.000).The BK value of patients before treatment was 7.72 ng·mL~(-1),and after 7 days(6.61 ng·mL~(-1))and 14 days(5.98 ng·mL~(-1))decreased significantly(F = 30.025,P = 0.000).CGRP decreased after treatment,but multiple comparisons showed that there were significant differences between pretreatment and 7 days' treatment(P = 0.015),between pre-treatment and 14 days' treatment(P = 0.002),while there was no significant difference between 7 days' and 14 days' treatments(P = 0.469).TRPA1 decreased after treatment,and multiple comparisons showed no difference between pre-treatment and 7 days' treatment(P = 0.243),significant statistical significance between pre-treatment and 14 day' of treatment(P = 0.000),between 7 days' and 14 days' treatments(P = 0.000).Conclusion:Bugu Keli can effectively relieve chronic pain in patients with osteoarthritis,which may inhibit peripheral sensitization and central sensitization by inhibiting the expression or secretion of TRPA1,CGRP and BK.
Objective:By observing the effects of Bugu Keli(补骨颗粒)on chronic pain,BK,CGRP and TRPA1 in patients with osteoarthritis,to explore the its mechanism,so as to provide evidence for clinical prevention and treatment.Methods:Forty patients with knee joint pain were recruited and diagnosed as unilateral or bilateral knee osteoarthritis according to the criteria of American Rheumatology Society.Then they were diagnosed as bone bi(of kidney deficiency and blood stasis type)in terms of The Criteria of Diagnosis and Curative Effect of Osteoarthritis.The patients were given Chinese medicine for tonifying kidney and activating blood circulation strictly and on time.Before taking medicine,the seventh day and the fourteenth day after that,VAS was used to assess the rest pain of knee joint.At the same time,3 ～ 4 mL venous blood samples were taken for TRPA1,CGRP and BK detection.All the detection values were recorded in the pre-set tables and statistically analyzed with software SPSS 20.0.Results:A total of 32 patients were treated with Chinese medicine.The VAS score of rest pain before oral administration was 54.38.The average resting pain of patients after 7 days(44.69 points)and 14 days(32.81 points)was significantly relieved(F = 44.323,P = 0.000).The BK value of patients before treatment was 7.72 ng·mL~(-1),and after 7 days(6.61 ng·mL~(-1))and 14 days(5.98 ng·mL~(-1))decreased significantly(F = 30.025,P = 0.000).CGRP decreased after treatment,but multiple comparisons showed that there were significant differences between pretreatment and 7 days' treatment(P = 0.015),between pre-treatment and 14 days' treatment(P = 0.002),while there was no significant difference between 7 days' and 14 days' treatments(P = 0.469).TRPA1 decreased after treatment,and multiple comparisons showed no difference between pre-treatment and 7 days' treatment(P = 0.243),significant statistical significance between pre-treatment and 14 day' of treatment(P = 0.000),between 7 days' and 14 days' treatments(P = 0.000).Conclusion:Bugu Keli can effectively relieve chronic pain in patients with osteoarthritis,which may inhibit peripheral sensitization and central sensitization by inhibiting the expression or secretion of TRPA1,CGRP and BK.
引文
[1]中华中医药学会.骨性关节炎[J].风湿病与关节炎,2013,2(2):71-72.
[2]FELSON DT,HODGSON R.Identifying and treating preclinical and early osteoarthritis[J].Rheum Dis Clin North Am,2014,40(4):699-710.
[3]SKOU ST,GRAVEN-NIELSEN T,RASMUSSEN S,et al.Widespread sensitization in patients with chronic pain after revision total knee arthroplasty[J].Pain,2013,154(9):1588-1594.
[4]AITKEN D,LASLETT LL,CAI G,et al.A protocol for a multicentre,randomised,double-blind,placebo-controlled trial to compare the effect of annual infusions of zoledronic acid to placebo on knee structural change and knee pain over 24 months in knee osteoarthritis patients ZAP2[J].BMC Musculoskelet Disord,2018,19(1):217.
[5]VILELA CA,DA SILVA MORAIS A,PINA S,et al.Clinical Trials and Management of Osteochondral Lesions[J].Adv Exp Med Biol,2018,1058(1):391-413.
[6]DAR QA,SCHOTT EM,CATHELINE SE,et al.Daily oral consumption of hydrolyzed type 1 collagen is chondroprotective and anti-inflammatory in murine posttraumatic osteoarthritis[J].PLoS One,2017,12(4):e0174705.
[7]田惠萍,刘莹,王海洋,等.膝骨关节炎的中医药治疗临床研究进展[J].风湿病与关节炎,2018,7(1):67-71.
[8]LIU B,TAI Y,CACERES AI,et al.Oxidized Phospholipid Ox PAPC Activates TRPA1 and Contributes to Chronic Inflammatory Pain in Mice[J].PLoS One,2016,11(11):e0165200.
[9]NAZEMPOUR A,VAN WIE BJ.Chondrocytes,Mesenchymal Stem Cells,and Their Combination in Articular CartilageRegenerative Medicine[J].Ann Biomed Eng,2016,44(5):1325-1354.
[10]BELO JN,BERGER MY,KOES BW,et al.The prognostic value of the clinical ACR classification criteria of knee osteoarthritis for persisting knee complaints and increase of disability in general practice[J].Osteoarthritis Cartilage,2009,17(10):1288-1292.
[11]国家中医药管理局.中医病证诊断疗效标准[M].南京:南京大学出版社,1999:33.
[12]HA CW,PARK YB,MIN BW,et al.Prospective,randomized,double-blinded,double-dummy and multicenter phase IV clinical study comparing the efficacy and safety of PG201(Layla)and SKI306X in patients with osteoarthritis[J].J Ethnopharmacol,2016,181(1):1-7.
[13]史鹏博,赵如意,赵利敬,等.膝骨关节炎疼痛机制研究进展[J].风湿病与关节炎,2016,5(3):63-66.
[14]DE OLIVEIRA VL,SILVA JA,SERRA AJ,et al.Photobiomodulation therapy in the modulation of inflammatory mediators and bradykinin receptors in an experimental model of acute osteoarthritis[J].Lasers Med Sci,2017,32(1):87-94.
[15]UENG YF,LU CK,YANG SH,et al.Potentiation of the anticoagulation effect of warfarin by the herbal remedy Shu-Jing-Hwo-Shiee-Tang in rats:The dosing regimen and pharmacokinetic interaction[J].Drug Metab Pharmacokinet,2017,32(1):85-91.
[16]LU Y,PIPLANI H,MCALLISTER SL,et al.Transient Receptor Potential Ankyrin 1 Activation within the Cardiac Myocyte Limits Ischemia-reperfusion Injury in Rodents[J].Anesthesiology,2016,125(6):1171-1180.
[17]FERNANDES ES,RUSSELL FA,ALAWI KM,et al.Environmental cold exposure increases blood flow and affects pain sensitivity in the knee joints of CFA-induced arthritic mice in a TRPA1-dependent manner[J].Arthritis Res Ther,2016,18(1):7.
[18]SYX D,TRAN PB,MILLER RE,et al.Peripheral Mechanisms Contributing to Osteoarthritis Pain[J].Curr Rheumatol Rep,2018,20(2):9.
[19]OTIS C,GUILLOT M,MOREAU M,et al.Spinal neuropeptide modulation,functional assessment and cartilage lesions in a monosodium iodoacetate rat model of osteoarthritis[J].Neuropeptides,2017(65):56-62.
[20]ICHISEKI T,SHIMAZAKI M,UEDA Y,et al.Intraarticularly-Injected Mesenchymal Stem Cells Stimulate Anti-Inflammatory Molecules and Inhibit Pain Related Protein and Chondrolytic Enzymes in a Monoiodoacetate-Induced Rat Arthritis Model[J].Int J Mol Sci,2018,19(1):203.
[21]ANDERSEN HH,LO VS,GAZERANI P,et al.Dose-response study of topical allyl isothiocyanate(mustard oil)as a human surrogate model of pain,hyperalgesia,and neurogenic inflammation[J].Pain,2017,158(9):1723-1732.
[22]MEMON T,CHASE K,LEAVITT LS,et al.TRPA1 expression levels and excitability brake by KV channels influence cold sensitivity of TRPA1-expressing neurons[J].Neuroscience,2017,353:76-86.
[23]HORVáTHá,TéKUS V,BOROS M,et al.Transient receptor potential ankyrin 1(TRPA1)receptor is involved in chronic arthritis:in vivo study using TR-PA1-deficient mice[J].Arthritis Res Ther,2016,18(1):6.
[24]MOILANEN LJ,H?M?L?INEN M,NUMMENMAAE,et al.Monosodium iodoacetate-induced inflammation and joint pain are reduced in TRPA1 deficient mice-potential role of TRPA1 in osteoarthritis[J].Osteoarthritis Cartilage,2015,23(11):2017-2026.
[25]NIANHU L,LEI X,SHENG YI,et al.Effect of Bushenhuoxue formula on interleukin-1 beta and discoidin domain receptor 2 levels in a rat model of osteoarthritis[J].J Tradit Chin Med,2015,35(2):192-196.
[26]LIU W,WU Y,LIU X,et al.Metabolic regulatory and anti-oxidative effects of modified Bushen Huoxue decoction on experimental rabbit model of osteoarthritis[J].Chin J Integr Med,2013,19(6):459-463.
[27]SUN D,YAN Q,XU X,et al.LC-MS/MS analysis and evaluation of the anti-inflammatory activity of components from BushenHuoxue decoction[J].Pharm Biol,2017,55(1):937-945.
[2]FELSON DT,HODGSON R.Identifying and treating preclinical and early osteoarthritis[J].Rheum Dis Clin North Am,2014,40(4):699-710.
[3]SKOU ST,GRAVEN-NIELSEN T,RASMUSSEN S,et al.Widespread sensitization in patients with chronic pain after revision total knee arthroplasty[J].Pain,2013,154(9):1588-1594.
[4]AITKEN D,LASLETT LL,CAI G,et al.A protocol for a multicentre,randomised,double-blind,placebo-controlled trial to compare the effect of annual infusions of zoledronic acid to placebo on knee structural change and knee pain over 24 months in knee osteoarthritis patients ZAP2[J].BMC Musculoskelet Disord,2018,19(1):217.
[5]VILELA CA,DA SILVA MORAIS A,PINA S,et al.Clinical Trials and Management of Osteochondral Lesions[J].Adv Exp Med Biol,2018,1058(1):391-413.
[6]DAR QA,SCHOTT EM,CATHELINE SE,et al.Daily oral consumption of hydrolyzed type 1 collagen is chondroprotective and anti-inflammatory in murine posttraumatic osteoarthritis[J].PLoS One,2017,12(4):e0174705.
[7]田惠萍,刘莹,王海洋,等.膝骨关节炎的中医药治疗临床研究进展[J].风湿病与关节炎,2018,7(1):67-71.
[8]LIU B,TAI Y,CACERES AI,et al.Oxidized Phospholipid Ox PAPC Activates TRPA1 and Contributes to Chronic Inflammatory Pain in Mice[J].PLoS One,2016,11(11):e0165200.
[9]NAZEMPOUR A,VAN WIE BJ.Chondrocytes,Mesenchymal Stem Cells,and Their Combination in Articular CartilageRegenerative Medicine[J].Ann Biomed Eng,2016,44(5):1325-1354.
[10]BELO JN,BERGER MY,KOES BW,et al.The prognostic value of the clinical ACR classification criteria of knee osteoarthritis for persisting knee complaints and increase of disability in general practice[J].Osteoarthritis Cartilage,2009,17(10):1288-1292.
[11]国家中医药管理局.中医病证诊断疗效标准[M].南京:南京大学出版社,1999:33.
[12]HA CW,PARK YB,MIN BW,et al.Prospective,randomized,double-blinded,double-dummy and multicenter phase IV clinical study comparing the efficacy and safety of PG201(Layla)and SKI306X in patients with osteoarthritis[J].J Ethnopharmacol,2016,181(1):1-7.
[13]史鹏博,赵如意,赵利敬,等.膝骨关节炎疼痛机制研究进展[J].风湿病与关节炎,2016,5(3):63-66.
[14]DE OLIVEIRA VL,SILVA JA,SERRA AJ,et al.Photobiomodulation therapy in the modulation of inflammatory mediators and bradykinin receptors in an experimental model of acute osteoarthritis[J].Lasers Med Sci,2017,32(1):87-94.
[15]UENG YF,LU CK,YANG SH,et al.Potentiation of the anticoagulation effect of warfarin by the herbal remedy Shu-Jing-Hwo-Shiee-Tang in rats:The dosing regimen and pharmacokinetic interaction[J].Drug Metab Pharmacokinet,2017,32(1):85-91.
[16]LU Y,PIPLANI H,MCALLISTER SL,et al.Transient Receptor Potential Ankyrin 1 Activation within the Cardiac Myocyte Limits Ischemia-reperfusion Injury in Rodents[J].Anesthesiology,2016,125(6):1171-1180.
[17]FERNANDES ES,RUSSELL FA,ALAWI KM,et al.Environmental cold exposure increases blood flow and affects pain sensitivity in the knee joints of CFA-induced arthritic mice in a TRPA1-dependent manner[J].Arthritis Res Ther,2016,18(1):7.
[18]SYX D,TRAN PB,MILLER RE,et al.Peripheral Mechanisms Contributing to Osteoarthritis Pain[J].Curr Rheumatol Rep,2018,20(2):9.
[19]OTIS C,GUILLOT M,MOREAU M,et al.Spinal neuropeptide modulation,functional assessment and cartilage lesions in a monosodium iodoacetate rat model of osteoarthritis[J].Neuropeptides,2017(65):56-62.
[20]ICHISEKI T,SHIMAZAKI M,UEDA Y,et al.Intraarticularly-Injected Mesenchymal Stem Cells Stimulate Anti-Inflammatory Molecules and Inhibit Pain Related Protein and Chondrolytic Enzymes in a Monoiodoacetate-Induced Rat Arthritis Model[J].Int J Mol Sci,2018,19(1):203.
[21]ANDERSEN HH,LO VS,GAZERANI P,et al.Dose-response study of topical allyl isothiocyanate(mustard oil)as a human surrogate model of pain,hyperalgesia,and neurogenic inflammation[J].Pain,2017,158(9):1723-1732.
[22]MEMON T,CHASE K,LEAVITT LS,et al.TRPA1 expression levels and excitability brake by KV channels influence cold sensitivity of TRPA1-expressing neurons[J].Neuroscience,2017,353:76-86.
[23]HORVáTHá,TéKUS V,BOROS M,et al.Transient receptor potential ankyrin 1(TRPA1)receptor is involved in chronic arthritis:in vivo study using TR-PA1-deficient mice[J].Arthritis Res Ther,2016,18(1):6.
[24]MOILANEN LJ,H?M?L?INEN M,NUMMENMAAE,et al.Monosodium iodoacetate-induced inflammation and joint pain are reduced in TRPA1 deficient mice-potential role of TRPA1 in osteoarthritis[J].Osteoarthritis Cartilage,2015,23(11):2017-2026.
[25]NIANHU L,LEI X,SHENG YI,et al.Effect of Bushenhuoxue formula on interleukin-1 beta and discoidin domain receptor 2 levels in a rat model of osteoarthritis[J].J Tradit Chin Med,2015,35(2):192-196.
[26]LIU W,WU Y,LIU X,et al.Metabolic regulatory and anti-oxidative effects of modified Bushen Huoxue decoction on experimental rabbit model of osteoarthritis[J].Chin J Integr Med,2013,19(6):459-463.
[27]SUN D,YAN Q,XU X,et al.LC-MS/MS analysis and evaluation of the anti-inflammatory activity of components from BushenHuoxue decoction[J].Pharm Biol,2017,55(1):937-945.