电针治疗糖尿病周围神经损伤性疼痛的分子机制研究
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摘要
目的：
观察电针治疗糖尿病周围神经损伤性疼痛（diabetic peripheral neuropathic pain，DPNP）的效果，并探讨其可能的分子机制。
方法：
1、DPNP大鼠造模。体重在160-180g的雌性SD大鼠禁食10小时后按60mg/kg腹腔内注射链尿佐菌素(streptozotocin，STZ)，并于造模前及造模后1、2、3、4、6、8、10、12周分别测其体重、空腹血糖及后足底部机械痛敏的阈值，造模后2周空腹血糖>16.7mmol/L、2周时机械痛敏的阈值下降较基础值大于2g者为造模成功。
2、实验处理：DPNP大鼠造模成功后随机分为对照组、电针1组、电针2组、假电针组。电针1组接受4/12低频率与中频率交替、强度1MA、时长半小时的足三里穴位电针刺激。电针2组接受相同频率、强度、时长的膏肓穴位的电针刺激。假电针组接受足三里穴位半小时针刺，但不给于电刺激。对照组不接受任何处理。检测电针治疗当天及1周后各组治疗后30min、60min、120min、240min后足底机械痛敏阈值。同时检测电针1组治疗后每日同一时间点（电针治疗后120min）后足底机械痛敏阈值，直至阈值恢复至治疗前水平。
3、采用weston blot方法检测电针治疗前后DPNP大鼠L4-L6脊髓背根神经节（Dorsal root ganglions，DRGs）神经元中核因子κB (Nuclear factor kappa B，NF-κB)蛋白表达水平。
结果：
1、STZ腹腔注射后2周，大鼠空腹血糖明显升高，伴随体重下降，符合糖尿病标准。大鼠后足底机械痛敏阈值于STZ注射后1周后即出现明显下降趋势，在2-6周时达到一平台期，8周后呈现上升趋势，12周痛敏现象消失。
2、电针1组首次电针治疗后30min即出现足底机械阈值的上升，60min达到高峰后出现平台期，于120min呈现下降趋势。一次电针治疗镇痛时间可持续4天。再次接受电针治疗后于30min即进入平台期，且240min仍无明显下降趋势，与首次电针治疗相比，平台期提前，平台期持续时间及稳定性增加。
3、与对照组相比，DPNP大鼠后足投射的特异性背根神经节（L4-L6DRG）神经元中NF-κB的蛋白表达水平明显增加。与电针治疗前相比，治疗后NF-κB蛋白表达水平降低。
结论：
1、STZ能成功诱导DPNP大鼠模型。
2、4/12低频率与中频率交替、强度1mA、时长半小时足三里穴位的电针治疗有明显镇痛效果，镇痛效果可持续4天。多次电针治疗可延长镇痛时间、增强镇痛效果。
3、NF-κB参与DPNP发生，电针治疗可通过调控大鼠后足投射的特异性背根神经节神经元内NF-κB的水平而发挥镇痛作用。
Objective:
To study the mechanism of DPNP (diabetic peripheral neuropathy pain，DPNP). Toobserve the behavior changes of the DPNP rats before and after the electro-acupuncturetreatment and to explore its mechanism.
Method:
1DPNP rat model. female rats accepted intraperitoneal injection of60mg/kgstreptozotocin (STZ) after being fasted10hours before modeling, modeling1234681012weeks to measure their weight, fasting blood glucose and the mechanical threshold atthe bottom of foot.two weeks after modeling, the rats with fasting bloodglucose>16.7mmol/L, the threshold decreased two or more compared to baseline valueswere enrolled.
2, The models were randomly divided into control group, EA no1group, EA no2group, sham EA group. The EA no1group received a half-hourlong Zusanlielectroacupuncture stimulation with alternating4/12low-frequency and frequency,intensity1MA, then the EA no2group received Gaohuangshu acupoint electricalstimulation with the same frequency, intensity, duration. Sham EA group received Zusanlihalf-hour acupuncture without electrical stimulation. The control group did not receive anytreatment. To obtain the30min,60min,120min,240min foot mechanical thresholds ofcontrol group, EA no1group, EA no2group, sham EA group after the first and the secondtreatment. to measure the mechanical thresholds at the same time with the former isequivalent to120min time point till its effection disappeared.
3, the western blot.To compare the experimental rats and normal control group ratsspinal ganglia expression of nuclear factor kappa B (nuclear factor kappa B, NF-κB) in themolecular level.
Results:
1the weight and the echanical threshold of rats these with STZ injection,wassignificantly lower than the rats without STZ injection, then the fasting plasma glucose wassignificantly higher.the mechanical threshold of the the STZ rats shows a clear downwardtrend at1week,a plateau at2-6weeks,a rise at8week,and the disappearment of allodynicphenomenon at12week.
2the mechanical threshold of EA no1group was significantly increased. after thefirst day of the EA, the mechanical threshold of no1EA group appears shows a rise at30min,a peak at60min then a downward trend at120min. the Analgesic effect of electricneedle treatment can last up to4days. the mechanical threshold of the rats which acceptedthe second EA treatment shows the platform at30min and no clear downward trend.again aweek after a group of EA electro-acupuncture treatment of plantarmechanical thresholdthan the control group was significantly increased.
3the NF-κB molecule expression level of the DPNP rats was significantly increasedcompareing with normal control group.then the expression level of NF-κB in EA groupDPNP rat dorsal root ganglion were markedly lower.
Conclusion:
1SD rats2weeks after the injection of STZ can reach the standards of DPNP rats,and good stability in the model in2-6weeks.
2,4/12low-frequency and frequency of alternating strength1MA long half-hour ofZusanli electroacupuncture treatment has a significant analgesic effect, and the analgesiceffec can last up to4days.multiple EA treatment can enhance the duration of analgesia
3, DPNP, in the rat pain molecular substances in the participation of NF-κB.theNF-κB in the regulation of rat spinalganglion may be the target of the electro-acupuncturetreatment.
观察电针治疗糖尿病周围神经损伤性疼痛（diabetic peripheral neuropathic pain，DPNP）的效果，并探讨其可能的分子机制。
方法：
1、DPNP大鼠造模。体重在160-180g的雌性SD大鼠禁食10小时后按60mg/kg腹腔内注射链尿佐菌素(streptozotocin，STZ)，并于造模前及造模后1、2、3、4、6、8、10、12周分别测其体重、空腹血糖及后足底部机械痛敏的阈值，造模后2周空腹血糖>16.7mmol/L、2周时机械痛敏的阈值下降较基础值大于2g者为造模成功。
2、实验处理：DPNP大鼠造模成功后随机分为对照组、电针1组、电针2组、假电针组。电针1组接受4/12低频率与中频率交替、强度1MA、时长半小时的足三里穴位电针刺激。电针2组接受相同频率、强度、时长的膏肓穴位的电针刺激。假电针组接受足三里穴位半小时针刺，但不给于电刺激。对照组不接受任何处理。检测电针治疗当天及1周后各组治疗后30min、60min、120min、240min后足底机械痛敏阈值。同时检测电针1组治疗后每日同一时间点（电针治疗后120min）后足底机械痛敏阈值，直至阈值恢复至治疗前水平。
3、采用weston blot方法检测电针治疗前后DPNP大鼠L4-L6脊髓背根神经节（Dorsal root ganglions，DRGs）神经元中核因子κB (Nuclear factor kappa B，NF-κB)蛋白表达水平。
结果：
1、STZ腹腔注射后2周，大鼠空腹血糖明显升高，伴随体重下降，符合糖尿病标准。大鼠后足底机械痛敏阈值于STZ注射后1周后即出现明显下降趋势，在2-6周时达到一平台期，8周后呈现上升趋势，12周痛敏现象消失。
2、电针1组首次电针治疗后30min即出现足底机械阈值的上升，60min达到高峰后出现平台期，于120min呈现下降趋势。一次电针治疗镇痛时间可持续4天。再次接受电针治疗后于30min即进入平台期，且240min仍无明显下降趋势，与首次电针治疗相比，平台期提前，平台期持续时间及稳定性增加。
3、与对照组相比，DPNP大鼠后足投射的特异性背根神经节（L4-L6DRG）神经元中NF-κB的蛋白表达水平明显增加。与电针治疗前相比，治疗后NF-κB蛋白表达水平降低。
结论：
1、STZ能成功诱导DPNP大鼠模型。
2、4/12低频率与中频率交替、强度1mA、时长半小时足三里穴位的电针治疗有明显镇痛效果，镇痛效果可持续4天。多次电针治疗可延长镇痛时间、增强镇痛效果。
3、NF-κB参与DPNP发生，电针治疗可通过调控大鼠后足投射的特异性背根神经节神经元内NF-κB的水平而发挥镇痛作用。
Objective:
To study the mechanism of DPNP (diabetic peripheral neuropathy pain，DPNP). Toobserve the behavior changes of the DPNP rats before and after the electro-acupuncturetreatment and to explore its mechanism.
Method:
1DPNP rat model. female rats accepted intraperitoneal injection of60mg/kgstreptozotocin (STZ) after being fasted10hours before modeling, modeling1234681012weeks to measure their weight, fasting blood glucose and the mechanical threshold atthe bottom of foot.two weeks after modeling, the rats with fasting bloodglucose>16.7mmol/L, the threshold decreased two or more compared to baseline valueswere enrolled.
2, The models were randomly divided into control group, EA no1group, EA no2group, sham EA group. The EA no1group received a half-hourlong Zusanlielectroacupuncture stimulation with alternating4/12low-frequency and frequency,intensity1MA, then the EA no2group received Gaohuangshu acupoint electricalstimulation with the same frequency, intensity, duration. Sham EA group received Zusanlihalf-hour acupuncture without electrical stimulation. The control group did not receive anytreatment. To obtain the30min,60min,120min,240min foot mechanical thresholds ofcontrol group, EA no1group, EA no2group, sham EA group after the first and the secondtreatment. to measure the mechanical thresholds at the same time with the former isequivalent to120min time point till its effection disappeared.
3, the western blot.To compare the experimental rats and normal control group ratsspinal ganglia expression of nuclear factor kappa B (nuclear factor kappa B, NF-κB) in themolecular level.
Results:
1the weight and the echanical threshold of rats these with STZ injection,wassignificantly lower than the rats without STZ injection, then the fasting plasma glucose wassignificantly higher.the mechanical threshold of the the STZ rats shows a clear downwardtrend at1week,a plateau at2-6weeks,a rise at8week,and the disappearment of allodynicphenomenon at12week.
2the mechanical threshold of EA no1group was significantly increased. after thefirst day of the EA, the mechanical threshold of no1EA group appears shows a rise at30min,a peak at60min then a downward trend at120min. the Analgesic effect of electricneedle treatment can last up to4days. the mechanical threshold of the rats which acceptedthe second EA treatment shows the platform at30min and no clear downward trend.again aweek after a group of EA electro-acupuncture treatment of plantarmechanical thresholdthan the control group was significantly increased.
3the NF-κB molecule expression level of the DPNP rats was significantly increasedcompareing with normal control group.then the expression level of NF-κB in EA groupDPNP rat dorsal root ganglion were markedly lower.
Conclusion:
1SD rats2weeks after the injection of STZ can reach the standards of DPNP rats,and good stability in the model in2-6weeks.
2,4/12low-frequency and frequency of alternating strength1MA long half-hour ofZusanli electroacupuncture treatment has a significant analgesic effect, and the analgesiceffec can last up to4days.multiple EA treatment can enhance the duration of analgesia
3, DPNP, in the rat pain molecular substances in the participation of NF-κB.theNF-κB in the regulation of rat spinalganglion may be the target of the electro-acupuncturetreatment.
引文
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