三叉神经痛动物模型的建立及三叉神经脊束核尾侧亚核神经元的机能学研究
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摘要
三叉神经痛（trigeminal neuralgia, TN）是累及面部三叉神经一支或几支感觉分布区、反复发作的阵发性剧烈疼痛，目前病因和发病机制尚不明确。本论文根据临床三叉神经痛常见的血管压迫病因，建立了一种三叉神经痛大鼠压迫模型并进行相关研究。主要结果如下：
1.建立大鼠三叉神经痛压迫模型
16只成年SD大鼠（200-220g）随机分为TN模型组（n=8）和假手术组（n=8）。模型组大鼠通过手术暴露右侧眼眶底部的眶下神经，用一段细塑料导丝沿眶下神经方向，从眶下裂逆行插入颅内到达并压迫三叉神经根部。术后TN组大鼠口面部机械痛敏、热痛敏和面部理毛行为增加。采用免疫组织化学染色观察到，TN组大鼠同侧三叉神经根区胶质纤维酸蛋白（glial fibrillary acidic protein, GFAP）阳性的星形胶质细胞突起大量增生；三叉神经脊束核尾侧亚核（caudal subnucleus of the spinaltrigeminal nucleus, Vc）内可见异凝集素B4（isolectin B4, IB4）及P物质（substanceP, SP）、降钙素基因相关肽（calcitonin gene-related peptide, CGRP）阳性终末在三叉神经根压迫损伤后均显著减少。这些结果说明慢性压迫大鼠眶下神经可有效地诱导口面部持续性的三叉神经痛样行为表现。
2.全细胞膜片钳技术检测三叉神经痛模型大鼠三叉神经脊束核尾侧亚核神经元兴奋性的改变
运用全细胞膜片钳电压钳技术，观察12只SD成年大鼠（模型组n=6,空白组n=6）Vc中间神经元的自发兴奋性突触后电流（spontaneous excitatory postsynaticcurrents, sEPSCs）。结果表明TN模型组大鼠Vc神经元的sEPSCs的频率和幅度比对照组增多，提示三叉神经根慢性压迫损伤引起的Vc神经元兴奋性增强，其突触传递的增强机制既包括突触前释放率的增加，也有突触后受体反应增强。
3.在体细胞外记录正常大鼠和三叉神经痛模型大鼠三叉神经脊束核尾侧亚核神经元的电生理学特性
采用在体细胞外记录技术，在模型组和对照组，分别记录Vc神经元的自发放电，并在口面部感受野给予机械刺激（刷、夹、压）的同时，记录神经元的诱发放电情况。结果表明，TN模型组大鼠Vc神经元自发放电频率以及口面部感受野给予机械刺激后诱发的放电频率均比对照组明显增加。
本论文的研究结果表明：大鼠三叉神经根慢性压迫损伤后，表现出明显的机械痛敏、热痛敏和自发痛行为，三叉神经根区GFAP阳性的星形胶质细胞突起大量增生，Vc内的神经递质（SP/CGRP）及IB4的表达明显减少，Vc中间神经元的兴奋性明显增强，说明用该方法诱导建立的一种新型三叉神经痛大鼠模型是可靠的。
Trigeminal neuralgia (TN) is a recurrent paroxysmal, severe facial pain in thedistribution of one or more branches of the trigeminal nerve. The etiology andpathogenesis of TN is still unclear. In this research, we established an anminal model ofTN induced by chronic compression injury of trigeminal nerve root, which was based onthe clinical common cause of TN by vascular compression. The main results of our studyare as follows:
1. Establishment of the rat model of TN
16adult male Sprague-Dawley rats (200-220g) were randomly divided into2groups: TN group that received chronic compression of the trigeminal nerve root (n=8),and sham operation group that received sham operation without compression (n=8). Asmall plastic filament was retrogressively inserted into the intracalvarium from theinferior orbital fissure until it reached the trigeminal nerve root for compression in TNgroup. The orofacial mechanical allodynia, heat hyperalgesia and facegrooming behaviorof rats in the TN group were obviously increased after the trigeminal root injury. Inimmunohistochemical staining, glial fibrillary acidic protein (GFAP) positive astrocyticprocesses were progressively proliferated in the ipsilateral trigeminal root entry zone(TREZ) of the TN group, and the positive immunoreactive primary afferent terminals ofisolectin B4(IB4), substance P (SP) and calcitonin gene-related peptide (CGRP) in thecaudal subnucleus of the spinal trigeminal nucleus (Vc) were significantly reduced after the trigeminal nerve root compression injury. These results indicated that chroniccompression of the trigeminal nerve root in rats could effectively induce persistentorofacial neuropathic pain behaviors.
2. Whole-cell patch clamp technique for detecting Vc neuronal excitability
Using whole-cell patch clamp voltage clamp technique to record the spontaneousexcitatory postsynaptic currents (sEPSCs) of Vc neurons in the rats (TN group, n=6;control group, n=6). The results showed that the frequency and amplitude of sEPSCs ofVc neurons in TN model rats were significantly higher than control group, which impliedthe Vc neuronal excitability was increased in the TN model animal. The enhancedsynaptic transmission mechanism may include both the increase of the presynapticrelease rate and postsynaptic receptor response enhancement.
3. The extracellular single-unit recording of Vc neuronal electrophysiologicalproperties in the control group and TN group rats
The neurons spontaneous discharges and evoked discharges induced by mechanicalstimulation (brush, press, and pinch) in the orofacial receptive field were recorded byextracellular single-unit recording technique in the TN group and control group. Theresults showed that the frequencies of spontaneous discharges and evoked dischargesinduced by mechanical stimulation in TN group were significantly increased.
The results in our study showed that, chronic compression injury of the trigeminalnerve root in rats could induce significant mechanical hyperalgesia, thermal hyperalgesiaand spontaneous pain behavior, GFAP positive astrocytic processes were largelyproliferated in the TREZ, both neurotransmitters (SP/CGRP) and IB4expression in Vcneurons were decreased, and Vc neuronal excitability was significantly increased. Ourresults suggested that chronic compression injury of the trigeminal nerve root couldinduce a new reliable animal model of TN in rats.
1.建立大鼠三叉神经痛压迫模型
16只成年SD大鼠（200-220g）随机分为TN模型组（n=8）和假手术组（n=8）。模型组大鼠通过手术暴露右侧眼眶底部的眶下神经，用一段细塑料导丝沿眶下神经方向，从眶下裂逆行插入颅内到达并压迫三叉神经根部。术后TN组大鼠口面部机械痛敏、热痛敏和面部理毛行为增加。采用免疫组织化学染色观察到，TN组大鼠同侧三叉神经根区胶质纤维酸蛋白（glial fibrillary acidic protein, GFAP）阳性的星形胶质细胞突起大量增生；三叉神经脊束核尾侧亚核（caudal subnucleus of the spinaltrigeminal nucleus, Vc）内可见异凝集素B4（isolectin B4, IB4）及P物质（substanceP, SP）、降钙素基因相关肽（calcitonin gene-related peptide, CGRP）阳性终末在三叉神经根压迫损伤后均显著减少。这些结果说明慢性压迫大鼠眶下神经可有效地诱导口面部持续性的三叉神经痛样行为表现。
2.全细胞膜片钳技术检测三叉神经痛模型大鼠三叉神经脊束核尾侧亚核神经元兴奋性的改变
运用全细胞膜片钳电压钳技术，观察12只SD成年大鼠（模型组n=6,空白组n=6）Vc中间神经元的自发兴奋性突触后电流（spontaneous excitatory postsynaticcurrents, sEPSCs）。结果表明TN模型组大鼠Vc神经元的sEPSCs的频率和幅度比对照组增多，提示三叉神经根慢性压迫损伤引起的Vc神经元兴奋性增强，其突触传递的增强机制既包括突触前释放率的增加，也有突触后受体反应增强。
3.在体细胞外记录正常大鼠和三叉神经痛模型大鼠三叉神经脊束核尾侧亚核神经元的电生理学特性
采用在体细胞外记录技术，在模型组和对照组，分别记录Vc神经元的自发放电，并在口面部感受野给予机械刺激（刷、夹、压）的同时，记录神经元的诱发放电情况。结果表明，TN模型组大鼠Vc神经元自发放电频率以及口面部感受野给予机械刺激后诱发的放电频率均比对照组明显增加。
本论文的研究结果表明：大鼠三叉神经根慢性压迫损伤后，表现出明显的机械痛敏、热痛敏和自发痛行为，三叉神经根区GFAP阳性的星形胶质细胞突起大量增生，Vc内的神经递质（SP/CGRP）及IB4的表达明显减少，Vc中间神经元的兴奋性明显增强，说明用该方法诱导建立的一种新型三叉神经痛大鼠模型是可靠的。
Trigeminal neuralgia (TN) is a recurrent paroxysmal, severe facial pain in thedistribution of one or more branches of the trigeminal nerve. The etiology andpathogenesis of TN is still unclear. In this research, we established an anminal model ofTN induced by chronic compression injury of trigeminal nerve root, which was based onthe clinical common cause of TN by vascular compression. The main results of our studyare as follows:
1. Establishment of the rat model of TN
16adult male Sprague-Dawley rats (200-220g) were randomly divided into2groups: TN group that received chronic compression of the trigeminal nerve root (n=8),and sham operation group that received sham operation without compression (n=8). Asmall plastic filament was retrogressively inserted into the intracalvarium from theinferior orbital fissure until it reached the trigeminal nerve root for compression in TNgroup. The orofacial mechanical allodynia, heat hyperalgesia and facegrooming behaviorof rats in the TN group were obviously increased after the trigeminal root injury. Inimmunohistochemical staining, glial fibrillary acidic protein (GFAP) positive astrocyticprocesses were progressively proliferated in the ipsilateral trigeminal root entry zone(TREZ) of the TN group, and the positive immunoreactive primary afferent terminals ofisolectin B4(IB4), substance P (SP) and calcitonin gene-related peptide (CGRP) in thecaudal subnucleus of the spinal trigeminal nucleus (Vc) were significantly reduced after the trigeminal nerve root compression injury. These results indicated that chroniccompression of the trigeminal nerve root in rats could effectively induce persistentorofacial neuropathic pain behaviors.
2. Whole-cell patch clamp technique for detecting Vc neuronal excitability
Using whole-cell patch clamp voltage clamp technique to record the spontaneousexcitatory postsynaptic currents (sEPSCs) of Vc neurons in the rats (TN group, n=6;control group, n=6). The results showed that the frequency and amplitude of sEPSCs ofVc neurons in TN model rats were significantly higher than control group, which impliedthe Vc neuronal excitability was increased in the TN model animal. The enhancedsynaptic transmission mechanism may include both the increase of the presynapticrelease rate and postsynaptic receptor response enhancement.
3. The extracellular single-unit recording of Vc neuronal electrophysiologicalproperties in the control group and TN group rats
The neurons spontaneous discharges and evoked discharges induced by mechanicalstimulation (brush, press, and pinch) in the orofacial receptive field were recorded byextracellular single-unit recording technique in the TN group and control group. Theresults showed that the frequencies of spontaneous discharges and evoked dischargesinduced by mechanical stimulation in TN group were significantly increased.
The results in our study showed that, chronic compression injury of the trigeminalnerve root in rats could induce significant mechanical hyperalgesia, thermal hyperalgesiaand spontaneous pain behavior, GFAP positive astrocytic processes were largelyproliferated in the TREZ, both neurotransmitters (SP/CGRP) and IB4expression in Vcneurons were decreased, and Vc neuronal excitability was significantly increased. Ourresults suggested that chronic compression injury of the trigeminal nerve root couldinduce a new reliable animal model of TN in rats.
引文
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[1] Hall, G.C., D. Carroll, D. Parry, et al. Epidemiology and treatment of neuropathicpain: the UK primary care perspective [J]. Pain,2006,122(1-2):156-62.
[2] Obermann, M. and Z. Katsarava. Update on trigeminal neuralgia [J]. Expert RevNeurother,2009,9(3):323-9.
[3] Nickel, F.T., F. Seifert, S. Lanz, et al. Mechanisms of neuropathic pain [J]. EurNeuropsychopharmacol,2012,22(2):81-91.
[4] Ikeda, H., T. Kiritoshi, and K. Murase. Synaptic plasticity in the spinal dorsalhorn [J]. Neurosci Res,2009,64(2):133-6.
[5] Kim, S.K., G. Kato, T. Ishikawa, et al. Phase-specific plasticity of synapticstructures in the somatosensory cortex of living mice during neuropathic pain [J].Mol Pain,2011,7:87.
[6] Udina, E., S. Cobianchi, I. Allodi, et al. Effects of activity-dependent strategies onregeneration and plasticity after peripheral nerve injuries [J]. Ann Anat,2011,193(4):347-53.
[7] Melemedjian, O.K. and T.J. Price. Dendritic spine plasticity as an underlyingmechanism of neuropathic pain: Commentary on Tan et al [J]. Exp Neurol,2011,233(2):740-4.
[8] Latremoliere, A. and C.J. Woolf. Central sensitization: a generator of painhypersensitivity by central neural plasticity [J]. J Pain,2009,10(9):895-926.
[9] Sandkuhler, J. Models and mechanisms of hyperalgesia and allodynia [J]. PhysiolRev,2009,89(2):707-58.
[10] Woolf, C.J. and M.W. Salter. Neuronal plasticity: increasing the gain in pain [J].Science,2000,288(5472):1765-9.
[11] Koerber, H.R., K. Mirnics, P.B. Brown, et al. Central sprouting and functionalplasticity of regenerated primary afferents [J]. J Neurosci,1994,14(6):3655-71.
[12] Lekan, H.A., S.M. Carlton, and R.E. Coggeshall. Sprouting of A beta fibers intolamina II of the rat dorsal horn in peripheral neuropathy [J]. Neurosci Lett,1996,208(3):147-50.
[13] Woolf, C.J., P. Shortland, and R.E. Coggeshall. Peripheral nerve injury triggerscentral sprouting of myelinated afferents [J]. Nature,1992,355(6355):75-8.
[14] Woolf, C.J. and Q. Ma. Nociceptors--noxious stimulus detectors [J]. Neuron,2007,55(3)353-64.
[15] Woolf, C.J. Central sensitization: implications for the diagnosis and treatment ofpain [J]. Pain,2011,152(3Suppl):2-15.
[16] Kim, S.K. and J. Nabekura. Rapid synaptic remodeling in the adultsomatosensory cortex following peripheral nerve injury and its association withneuropathic pain [J]. J Neurosci,2011,31(14):5477-82.
[17] Zhuo, M. Cortical excitation and chronic pain [J]. Trends Neurosci,2008,31(4):199-207.
[18] Ji, R.R., T. Kohno, K.A. Moore, et al. Central sensitization and LTP: do pain andmemory share similar mechanisms?[J]. Trends Neurosci,2003,26(12):696-705.
[19] Cooke, S.F. and T.V. Bliss. Plasticity in the human central nervous system [J].Brain,2006,129(Pt7):1659-73.
[20] Bliss, T.V. and S.F. Cooke. Long-term potentiation and long-term depression: aclinical perspective [J]. Clinics (Sao Paulo),2011,66Suppl:13-17.
[21] Love, S. and H.B. Coakham. Trigeminal neuralgia: pathology and pathogenesis[J]. Brain,2001,124(Pt12):2347-60.
[22] Marinkovic, S., V. Todorovic, H. Gibo, et al. The trigeminal vasculaturepathology in patients with neuralgia [J]. Headache,2007,47(9)1334-9.
[23] Ramesh, V.G. and G. Premkumar. An anatomical study of the neurovascularrelationships at the trigeminal root entry zone [J]. J Clin Neurosci,2009,16(7)934-6.
[24] Guy, N., M. Chalus, R. Dallel, et al. Both oral and caudal parts of the spinaltrigeminal nucleus project to the somatosensory thalamus in the rat [J]. Eur JNeurosci,2005,21(3):741-54.
[25] Toma, J.S., L.T. McPhail, and M.S. Ramer. Comparative postnatal developmentof spinal, trigeminal and vagal sensory root entry zones [J]. Int J Dev Neurosci,2006,24(6):373-88.