脊髓电刺激对神经病理性疼痛镇痛作用及相关机制研究
|
摘要
目的:探索脊髓电刺激(spinal cord stimulation, SCS)对小鼠神经病理性疼痛的镇痛作用并阐明相关机制。方法:30只健康成年雄性野生型CD1小鼠随机分为对照组(Sham)、坐骨神经结扎损伤组(chronic constriction injury, CCI)和治疗组(CCI+SCS),每组10只。通过行为学观察SCS对外周神经损伤引起的机械痛敏和热痛敏的缓解情况,以及对小鼠运动功能影响程度;采用电生理方法记录各组小鼠背根神经节(dorsal root ganglion, DRG)中小神经元的兴奋性;通过酶联免疫吸附试验测定DRG内炎性因子TNF-α的表达水平。结果:与对照组比较,CCI组小鼠机械痛阈值和热痛阈值明显降低(P <0.05)。治疗组与CCI造模组比较,SCS可提高小鼠的机械痛和热痛阈值。同时,各组转棒实验评分无差异。电生理及酶联免疫吸附试验结果提示外周神经损伤后,同侧小鼠背根神经节(dorsal root ganglion, DRG)神经元的兴奋性增强,同时DRG内TNF-α的释放增加,治疗组与CCI组比较,SCS可以明显抑制DRG神经元的兴奋性增强(P <0.05)和DRG内TNF-α的释放增加(P <0.05)。结论:SCS通过抑制外周神经损伤导致的DRG神经元的兴奋性增强,从而有效地减缓小鼠CCI导致的机械感觉过敏和热痛敏,并可减少CCI小鼠DRG中TNF-α的表达水平。
Objective: To investigate the analgesic effects of spinal cord stimulation(SCS) on neuropathic pain and explore the underlying mechanisms. Methods: Thirty healthy adult male CD1 mice were randomly divided into control group(Sham, n = 10), chronic constriction injury(CCI, n = 10), spinal cord stimulation treated group(CCI + SCS, n = 10). The withdrawal threshold(g) of mechanical allodynia and withdrawal latency(s)of thermal hyperalgesia induced by CCI were detected in each group at different time point. We also tested the motor ability of mice in rotarod test. The excitability of dorsal root ganglion(DRG) neurons and the expression level of TNF-α in DRG were measured by electrophysiological and ELISA methods, respectively. Results: The withdrawal threshold(g) and withdrawal latency(s) in CCI group were decreased significantly compared with control group(P < 0.05). SCS upregulated both withdrawal threshold(g) and withdrawal latency(s) compared to CCI group. There was no difference in the score of rotarod test between each group. We also found that the excitability of DRG neurons enhanced and the release of TNF-α in DRG potentiated in CCI group. However,compared with the CCI group, SCS significantly depressed the excitatory of DRG neurons(P < 0.05), and inhibited the release of TNF-α in DRG(P < 0.05). Conclusion: SCS decreases the excitability of DRG neurons and the expression of TNF-alpha in CCI group, and in turn relieves CCI-induced mechanical allodynia and thermal hyperalgesia. Meanwhile SCS does not change the motor function of mice.
Objective: To investigate the analgesic effects of spinal cord stimulation(SCS) on neuropathic pain and explore the underlying mechanisms. Methods: Thirty healthy adult male CD1 mice were randomly divided into control group(Sham, n = 10), chronic constriction injury(CCI, n = 10), spinal cord stimulation treated group(CCI + SCS, n = 10). The withdrawal threshold(g) of mechanical allodynia and withdrawal latency(s)of thermal hyperalgesia induced by CCI were detected in each group at different time point. We also tested the motor ability of mice in rotarod test. The excitability of dorsal root ganglion(DRG) neurons and the expression level of TNF-α in DRG were measured by electrophysiological and ELISA methods, respectively. Results: The withdrawal threshold(g) and withdrawal latency(s) in CCI group were decreased significantly compared with control group(P < 0.05). SCS upregulated both withdrawal threshold(g) and withdrawal latency(s) compared to CCI group. There was no difference in the score of rotarod test between each group. We also found that the excitability of DRG neurons enhanced and the release of TNF-α in DRG potentiated in CCI group. However,compared with the CCI group, SCS significantly depressed the excitatory of DRG neurons(P < 0.05), and inhibited the release of TNF-α in DRG(P < 0.05). Conclusion: SCS decreases the excitability of DRG neurons and the expression of TNF-alpha in CCI group, and in turn relieves CCI-induced mechanical allodynia and thermal hyperalgesia. Meanwhile SCS does not change the motor function of mice.
引文
[1]Epstein LJ,Palmieri M.Managing chronic pain with spinal cord stimulation[J].Mt Sinai J Med,201279(1):123-132.
[2]Kumar K,Taylor RS,Jacques L,et al.The effects of spinal cord stimulation in neuropathic pain are sustained:a 24-month follow-up of the prospective randomized controlled multicenter trial of the effectiveness of spinal cord stimulation[J].Neurosurgery,2008,63(4):762-770.
[3]Taylor RS,Ryan J,O'Donnell R,et al.The cost-effectiveness of spinal cord stimulation in the treatment of failed back surgery syndrome[J].Clin J Pain,201026(6):463-469.
[4]罗裕辉,熊东林,蒋劲,等.短时程脊髓电刺激治疗带状疱疹性神经痛的疗效观察[J].中国疼痛医学杂志,2016,22(2):118-122.
[5]Bennett GJ,Xie YK.A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man[J].Pain,1988,33(1):87-107.
[6]Smits H,van Kleef M,Joosten EA.Spinal cord stimulation of dorsal columns in a rat model of neuropathic pain:evidence for a segmental spinal mechanism of pain relief[J].Pain,2012,153(1):177-183.
[7]Ushio S,Egashira N,Sada H,et al.Goshajinkigan reduces oxaliplatin-induced peripheral neuropathy without affecting anti-tumour efficacy in rodents[J].Eur JCancer,2012,48(9):1407-1413.
[8]Chen G,Kim YH,Li H,et al.PD-L1 inhibits acute and chronic pain by suppressing nociceptive neuron activity via PD-1[J].Nat Neurosci,2017,20(7):917-926.
[9]Liu N,Zhang D,Zhu M,et al.Minocycline inhibits hyperpolarization-activated currents in rat substantia gelatinosa neurons[J].Neuropharmacology,201595:110-120.
[10]陈虹,李俊岑,党彦丽,等.电刺激对大鼠脊髓损伤后神经生长因子表达的影响[J].中国康复理论与实践,2012,(1):33-36.
[11]Peng JY,王佳昕.神经病理性疼痛由急性转化为慢性的机制:小胶质细胞和单核细胞协同作用[J].中国疼痛医学杂志,2017,23(1):73.
[12]Ji RR,Chamessian A,Zhang YQ.Pain regulation by non-neuronal cells and inflammation[J].Science,2016,354(6312):572-577.
[13]Gao YJ,Ji RR.Chemokines,neuronal-glial interactions,and central processing of neuropathic pain[J].Pharmocol Ther,2010,126(1):56-68.
[14]Zhang JM,An J.Cytokines,Inflammation and Pain[J].Int Anesthesiol Clin,2017,45(2):27-37.
[15]Zhou Z,Peng X,Hagshenas J,et al.A novel cell-cell signaling by microglial transmembrane TNF alpha with implications for neuropathic pain[J].Pain,2010,151(2):296-306.
[16]Milligan ED,Twining C,Chacur M,et al.Spinal glia and proinflammatory cytokines mediate mirror-image neuropathic pain in rats[J].J Neurosci,2003,23(3):1026-1040.
[17]Barnum CJ,Chen X,Chung J,et al.Peripheral administration of the selective inhibitor of soluble tumor necrosis factor(TNF)XPro(R)1595 attenuates nigral cell loss and glial activation in 6-OHDA hemiparkinsonian rats[J].J Parkinsons Dis,2014,4(3):349-360.
[18]Schafers M,Lee DH,Brors D,et al.Increased sensitivity of injured and adjacent uninjured rat primary sensory neurons to exogenous tumor necrosis factor-alpha after spinal nerve ligation[J].J Neurosci,2003,23(7):3028-3038.
[2]Kumar K,Taylor RS,Jacques L,et al.The effects of spinal cord stimulation in neuropathic pain are sustained:a 24-month follow-up of the prospective randomized controlled multicenter trial of the effectiveness of spinal cord stimulation[J].Neurosurgery,2008,63(4):762-770.
[3]Taylor RS,Ryan J,O'Donnell R,et al.The cost-effectiveness of spinal cord stimulation in the treatment of failed back surgery syndrome[J].Clin J Pain,201026(6):463-469.
[4]罗裕辉,熊东林,蒋劲,等.短时程脊髓电刺激治疗带状疱疹性神经痛的疗效观察[J].中国疼痛医学杂志,2016,22(2):118-122.
[5]Bennett GJ,Xie YK.A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man[J].Pain,1988,33(1):87-107.
[6]Smits H,van Kleef M,Joosten EA.Spinal cord stimulation of dorsal columns in a rat model of neuropathic pain:evidence for a segmental spinal mechanism of pain relief[J].Pain,2012,153(1):177-183.
[7]Ushio S,Egashira N,Sada H,et al.Goshajinkigan reduces oxaliplatin-induced peripheral neuropathy without affecting anti-tumour efficacy in rodents[J].Eur JCancer,2012,48(9):1407-1413.
[8]Chen G,Kim YH,Li H,et al.PD-L1 inhibits acute and chronic pain by suppressing nociceptive neuron activity via PD-1[J].Nat Neurosci,2017,20(7):917-926.
[9]Liu N,Zhang D,Zhu M,et al.Minocycline inhibits hyperpolarization-activated currents in rat substantia gelatinosa neurons[J].Neuropharmacology,201595:110-120.
[10]陈虹,李俊岑,党彦丽,等.电刺激对大鼠脊髓损伤后神经生长因子表达的影响[J].中国康复理论与实践,2012,(1):33-36.
[11]Peng JY,王佳昕.神经病理性疼痛由急性转化为慢性的机制:小胶质细胞和单核细胞协同作用[J].中国疼痛医学杂志,2017,23(1):73.
[12]Ji RR,Chamessian A,Zhang YQ.Pain regulation by non-neuronal cells and inflammation[J].Science,2016,354(6312):572-577.
[13]Gao YJ,Ji RR.Chemokines,neuronal-glial interactions,and central processing of neuropathic pain[J].Pharmocol Ther,2010,126(1):56-68.
[14]Zhang JM,An J.Cytokines,Inflammation and Pain[J].Int Anesthesiol Clin,2017,45(2):27-37.
[15]Zhou Z,Peng X,Hagshenas J,et al.A novel cell-cell signaling by microglial transmembrane TNF alpha with implications for neuropathic pain[J].Pain,2010,151(2):296-306.
[16]Milligan ED,Twining C,Chacur M,et al.Spinal glia and proinflammatory cytokines mediate mirror-image neuropathic pain in rats[J].J Neurosci,2003,23(3):1026-1040.
[17]Barnum CJ,Chen X,Chung J,et al.Peripheral administration of the selective inhibitor of soluble tumor necrosis factor(TNF)XPro(R)1595 attenuates nigral cell loss and glial activation in 6-OHDA hemiparkinsonian rats[J].J Parkinsons Dis,2014,4(3):349-360.
[18]Schafers M,Lee DH,Brors D,et al.Increased sensitivity of injured and adjacent uninjured rat primary sensory neurons to exogenous tumor necrosis factor-alpha after spinal nerve ligation[J].J Neurosci,2003,23(7):3028-3038.