摘要
目的:本研究通过建立坐骨神经慢性压榨模型(chronic constriction injury of the sciatic nerve model, CCI model),运用电生理学技术,研究γ-氨基丁酸(gamma-aminobutyric acid, GABA)介导的神经病理性痛大鼠背根神经节(dorsal root ganglion, DRG)神经元膜去极化反应,并探讨其可能机制,为进一步揭示神经病理性痛的发生机制提供一定的实验理论依据。
方法: 1)制作CCI模型,雄性SD大鼠(n=30只),随机分为三组,即正常对照组(n=10)假手术组(n=10)和CCI组(n=10),称重后腹腔注射1 %戊巴比妥纳(40 mg/kg)麻醉。分别在实验前及实验后0 d、1 d、3 d、5 d、7 d、9 d、11 d、14 d进行热板实验;2)取正常对照组和CCI组手术侧和非手术侧DRG,应用细胞内微电极记录技术,给予灌流GABA溶液(10~(-5)~10~(-3)mol/L),观察GABA对DRG神经元的作用。
结果:1)神经病理性痛大鼠手术侧的热刺激缩足反射潜伏期(paw withdrawal thermal latency, PWTL)比假手术组明显缩短,于术后第1 d开始降低,第7 d天降至最低(P﹤0.01);2)获得成功记录的细胞在正常对照组为63例,在CCI模型组手术侧为60例,在CCI模型组手术对侧为58例,所测得的静息电位值在正常对照组、CCI模型大鼠手术侧分别为-51±3 mV(n=63)、-49±4 mV(n=60)和-50±3 mV(n=58),统计学分析两组DRG标本的神经元静息膜电位之间差异没有统计学意义(P>0.05);3)同一浓度的GABA(10~(-5)~10~(-3) mol/L)引起的去极化反应在CCI模型组大鼠手术侧DRG明显小于正常对照组大鼠。各浓度GABA(10~(-5)~10~(-3) mol/L)引起两组大鼠DRG神经元膜去极化反应差异均有统计学意义(n≥6, P<0.05)。
结论: 1)大鼠坐骨神经慢性压榨模型可以作为一种稳定的神经病理性痛的研究模型;2)神经病理性痛时,GABA在初级感觉传入终末产生的突触前抑制作用被减弱,从而易化了伤害性信息(痛觉)的传递。
Objective: In this study,we firstly set up the chronic constriction injury of the sciatic nerve model of SD rats as the neuropathic pain model, and then used dorsal root ganglion (DRG) of this model to observe the role of GABA on DRG neurons and explore its mechanisms by using Intracellular recording technique in neuropathic conditions in order to provide with some experimental basis for further discussing the mechanism of neuropathic pain.
Methods: 1) CCI model: 30 male SD rats were randomly divided into three groups: control group (n=10), sham-operation group (n=10), and CCI group (n=10), sham and CCI groups were anesthsized under 1 % carbrital (40 mg/kg) and the hot plate test was given to measure paw withdrawal thermal latency (PTWL) at 0 d before operation and at 1 d, 3 d, 5 d, 7 d, 9 d, 11 d and 14 d after operation; 2) In freshly isolated rat DRG samples from control goup, CCI-Ispi group and CCI-contra group, we applied intracellular recording technique,and perfused GABA (10~(-5)~10~(-3) mol/L) to observe the role of GABA on DRG neurons in normal and neuropathic conditions.
Results: 1) The value of PWTL began to decrease at 1 d after operation, peaked at 7 d after operation and lasted through the whole experiment in neuropathic pain model. (P<0.01); 2) The rest membrane potential were -51±3 mV (n=63),-49±4 mV (n=60) and -50±3 mV (n=58) in control group, CCI Ipsi group and CCI contra group respectively.(P>0.05); 3) The depolarization responses induced by same concentration of GABA were lower in CCI group than in control group. Different concentration induced GABA depolarization responses in both groups showed significant difference. (n≥6, P<0.05)
Conclusions: 1) CCI animal model can be considered as an ideal model to explore the mechanism of neuropathic pain; 2) In neuropathic pain, GABA mediated presynaptic inhibition is attenuated which facilitates the nociceptive transmission;
引文
[1]高云,粱尚栋.神经病理痛动物模型及其在P2X受体介导痛觉研究中的作用.中国药理学通报, 2006, 22(11): 1310-1314.
[2] IASP Task Force on Taxonomy: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms IASP Press, Seattle; 1994.
[3] Chen H, Lamer TJ, Rho RH, Marshall KA, Sitzman BT, Ghazi SM, Brewer RP: Contemporary management of neuropathic pain for the primary care physician. Mayo Clin Proc 2004, 79:1533-1545.
[4] Wils on M. Overcoming the challenges of neuropathic pain. Nurs Stand, 2002, 16 (33) : 47-53.
[5] Woolf C J, Manni on R. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet, 1999, 353 (68) : 1959-1964.
[6] Millan MJ. The induction of pain: an integrative review. Prog Neurobiol. 1999, 57: 161-164.
[7] Chen Y, Shu Y&Zhao Z. Ectopic purinergic sensitivity develops at sites of chronic nerve constriction injury in rat. Neuroreport.1999, 10, 2779-2782.
[8] Liu X.Ectopic discharges and adrenergic sensitinity of sensory neurons after spinal nerve injury. Brain Res 1999, 849: 244-247.
[9] Sun Q. Characteristics of ectopic discharges and their relationship with neuropathic pain. Sheng Li Ke Xue Jin Zhan. 2004, 35(4):325-328.
[10] Dickenson A H.Neurobiology of neuropathic pain: Mode of action of anticonvulsants. Eur J Pain. 2002, 6(suppl A): 51-60.
[11] Devor M. Two models of cutaneous reinnervation following peripheral nerve injury. J Comp Neuro 1979, 185:211-220.
[12] Mclachlan E M.Peripheral nerve injury triggers noradrenergic sprouting within dorsal root ganglia. Nature 1993, 363:543-546.
[13] Zhang JM. Decreasing sympathetic sprouting in pathologic sensory ganglia: a new mechanism for treating neuropathic pain using lidocaine. Pain. 2004, 109(1-2):143-149.
[14] Michaelis M. Inflammatoru mediators sensitize acutely axotomized nerve fibers to mechanical stimulation in the rat.J Neurosci 1998, 18:7581-7587.
[15] Hokfelt T. Neuropeptides-An overview. Neuropharmacology 2000,39:1337-1356.
[16] Harper AA, Lawson SN. Conduction velocity is related to morphological cell type in ratdorsal root ganglion neurons. J Physiol, 1985, 359:31-46.
[17]杨鲲,王过渡,李云庆,等.电生理学特性得到确定的大鼠脊髓背根神经节细胞谷氨酸和P物质的共存.生理学报,1998, 50(4):453-459.
[18] M. Randic, H. Hecimovic, P.D. Ryu. Substance Pmodulates glutamate-induced currents in acutely isolated rat spinal dorsal horn neurons, Neurosci. Lett. 1990, 117: 74-80.
[19]司军强,李之望,樊友珍. P物质对大鼠新鲜分离DRG神经元NMDA及GABA激活电流的调制作用.神经科学,1996, 3: 114-119.
[20] K.Yamada, T. Akasu. Substance P suppresses GABAA receptor function via protein kinase C in primary sensory neurons of bullfrog, Journal of Physiology,1996,496:439-449.
[21] J.Q. Si, Z.Q.Zhang, C.X.Li, L.F.Wang, Y.L.Yang, Z.W.Li. Modulatory effect of substance P on GABA-activated currents from rat dorsal root ganglion. Acta Pharmacologica Sinica.2004, 20: 324-328.
[22] K.T. Ma, J.Q Si, Z.Q. Zhang, L. Zhao, P. Fan, J.L. Jin, X.Z. Li, L.Zhu. Modulatory effect of CCK-8S on GABA-induced depolarization from rat dorsal root ganglion. Brain research,2006, 1121: 66-75.
[23] J.C. Eccles, Presynaptic Inhibition in the Spinal Cord, Prog Brain Res, 1964, 12: 65-91.
[24] Carlton, S.M.,zhou, S., and Coggeshall,R.E. Peripheral GABA(A) receptors: Evidence for peripheral primary afferent depolarization. Neuroscience, 1999,93,713-722.
[25] Michel desrmenien, Paul Feltz, Guiseppe Occhipinti, el sel. Coexistence of GABAA and GABAB receptors on Aδand C afferents. Br. J. Pharmac,1984, 81:327-333.
[26] GALLAGHER, J.P., HIGASHI, H. & NISHI, S. Characterization and ionic basis of GABA-induced depolarization recorded in vitro from cat primary afferent neurons. J. Physiol. 1978, 275, 263-282.
[27] DESARMENIEN, M., FELTZ, P. & HEADLEY, P.M. Does glial uptake affect GABA responses? An intracellular study on rat dorsal root ganglion neurons in vitro. J. Physiol. 1980, 307, 163-182.
[28] DUNLAP, K. Two types ofγ-aminobutyric acid receptors on embryonic sensory neurones. Br. J. Pharmac.1981, 66, 579-585.
[29] Kendall, D.A., Browner, M.,and Enna,S.J.Comparison of the antinociceptive effectOf gamma-aminobutyric acid (GABA) agonists: Evidence for a cholinergic involvement. J. Pharmacol.Exp.Ther. 1982, 482–487.
[30] Levy,R.A.,and Proudfit, H.K.The analgesic action of baclofen. J. Pharmacol. Exp.Ther. 1977, 202: 437–445.
[31] Malan,T.P.,Heriberto,H.P.,and Poerreca,F.Spinal GABAA andGABAB receptor Pharm -acology in a rat model of neuropathic pain. Anesthesiology 2002, 96:1161–1167.
[32] Sands,S.A.,McCarson,K.E.,and Enna,S.J.Differential regulation of GABAB receptorsubunit expression and function. J.Pharmacol.Exp.Ther. 2003,305:191–196.
[33] Shafizadeh,M.,Semnanian,S., Zarrindast,M.R.,and Hashemi,B.Involvement of GABAB receptors in the antinociception induced by baclofen in the formalin test. Gen.Pharmacol. 1997,28: 611–615.
[34] Smith,G.D.,Harrison,S.M.,Birch,P.J.,Malcangio,M.,and Bowery, N. G. Increased Sensi -tivity to the antinociceptive activity of (+/-)baclofen in an animal model of chronic neuropathic, but not chronic in?ammatory hyperalgesia. Neuropharmacology. 1994, 33: 1103–1108.
[35] Thomas,D.A.,Navarrete,I.M.,Graham,B.A.,McGowan,M.K.,and Hammond,D.L. Antin -ociception produced by systemic R(+)‐baclofen hydrochloride is attenuated By CGP35348 administered to the spinal cord or ventromedia lmedulla of rats. Brain Res.1980, 718:129–137.
[36] Vaught,J.L.,Pelley,K.,Costa,L.G.,Settler,P.,and Enna,S.J.A comparison of the Anti -nociceptive responses to the GABA receptor agonists THIP and baclofen. Neuropha -rmacology.1985, 24:211–216.
[37] Zorn,S.H.,andEnna,S.J.GABA uptake inhibitors produce a greater antinociceptive Response in the mouse tail immersion assay than other types of GABAergic drugs. Life Sci.1985a, 37:1901–1912.
[38] Drew,G.M.,Siddall,P.J.,and Duggan,A.W.Mechanical allodynia following Contusion injury of the rat spinal cord is associated with loss ofGABAergic inhibition in The dorsal horn. Pain 2004, 109:379–388.
[39] Ibuki,T.,Hama,A.T.,Wang,X.T.,Pappas,G.D.,andSagen,J.(1997).Loss of GABA‐Immu -noreactivity in the spinal dorsal horn of rats with peripheral nerve injury and promotion of recovery by adrenal medullary grafts. Neuroscience .1997,76: 845–858.
[40] Miletic,G.,Draganic,P.,Pankratz,M.T.,and Miletic,V. Muscimol prevents long lasting potentiation of dorsal horn field potentials in rats with chronic constriction injury Exhi -biting decreased levels of the GABA transporter GAT-1. Pain .2003,105,347–353.
[41]Moore,K.A.,Kohno,T.,Karchewski,L.A.,Scholz,J.,Baba,H.,andWoolf,C.J. Partial peripheral nerve injury promotes a selective loss of GABAergic inhibition in the superficial dorsal horn of the spinalcord. J.Neurosci. 2002, 22,6724–6731.
[42] Somers,D.L.,and Clemente,F.R.Dorsal horn synaptosomal content of aspartate, glutamate, glycine andGABA are differentially altered following chronicconstriction injury to the rats ciatic nerve. Neurosci.Lett. 2002, 323:171–174.
[43] Polgar,E.,Hughes,D.I.,Riddell,J.S.,Maxwell,D.J.,Puskar,Z.,and Todd,A.J Selective loss of spinal GABAergic or glycinergic neurons is not necessary for development of thermal hyperalgesia in the chronic constriction injury model of neuropathic pain. Pain.2003,104;229–239.
[44] H. Ikeda and K.Murase.Glial Nitric Oxide-mediated Long-term presynaptic Facilitation revealed by optical imaging in rat spinal dorsal horn, the journal of Neuroscience, 2004,24: 9888-9896.
[45] Fukuoka T, Tokunaga A, Kondo E,et al. Change in mRNAs for neuropetides and GABAA receptor in dorsal root ganglion neurons in a rat experimetal neuropathic pain model. Pain.1998,78(1):13-26.
[46] Nicholas J.Brandon, Patrick Delmas, Josef T. Kittler et al. GABAA receptor phosphorylation and functional Modulation in Cortical Neurons by a Protein Kinase C-dependent pathway. The journal of biological chemistry, 2000, 275(49):38856-38862.
[47] Naik AK, Pathirathna S, Jevtovic-Todorovic V. GABA(A) receptor modulation in dorsal root ganglia in vivo affects chronic pain after nerve injury. Neuroscinece. 2008, 154(4): 1539-53
[48] Bennett GJ ,Xie YK. A peripheral mononeuropat hy in rat t hatproduces disorders of pain sensation like t hose seen in man. Pain , 1988, 33: 872107.
[49] Maves T J, Pechman P S, Gebhart G F, et al. Possible chemicalcontribution from chromic gut sutures p roduces disorders of pain sensation like those seen in man. Pain, 1993, 54 (1) : 57 -69.
[50]罗放,毕好生.神经病理性疼痛的背根神经节机制.《国外医学》麻醉学与复苏分册,2003,24(2): 68-69
[51] Si JQ, Li ZW, Hu HZ, et al.Inhibitory effect of baclofen on GABA-induced depolarization and GABA-activated current in primary sensory, Neuroscience, 1997,81(3): 821-827.
[52]祝利,王英姿,司军强,等.亚砷酸钠对大鼠离体坐骨神经干复合动作电位的影响.石河子大学学报(自然科学版),2007,25(1):65-68.
[53] Bowery,N.G.,and Enna,S.J. Gamma-amino butyricacid(B) receptors: First of the Functional metabotropic heterodimers. J.Pharmacol.Exp.Ther. 2000, 293: 2–7.
[54] Dirig,D.M.,andYaksh,T.L. Intrathecal baclofen and muscimol,but not midazolam, are antinociceptive using the rat-formalin model. J.Pharmacol.Exp.Ther.1995, 275: 219–227.
[55] Hill,R.C.,Maurer,R.,Buescher,H.H.,andRoemer,D.Analgesic properties of the GABA -mimetic THIP. Eur.J.Pharmacol. 1981, 69:221–224.
[56] Johnston,G.A. GABAA agonists as targets for drug development. Clin.Exp.Pharma -col.Physiol. 1992, 19: 73–78.
[57] Kaneko,M.,and Hammond,D.L.Role of spinal gamma-amino butyric acid Areceptors in formalin-induced nociception in the rat. J. Pharmacol.Exp.Ther. 1997, 282: 928–938.
[58] Kjaer,M.,and Nielsen,H.The analgesic effect of the GABA-agonist THIP in patients with chronic pain of malignant origin.A phase1–2 study. Br.J.Clin.Pharmacol. 1983, 16: 477–485.
[59] Malan,T.P.,Heriberto,H.P.,and Poerreca,F.Spinal GABAA and GABAB receptor Pharm -acology in a rat model of neuropathic pain. Anesthesiology 2002, 96:1161–1167.
[60] Rode,F.,Jensen,D.G.,Blackburn Munro,G.,and Bjerrum,O.J..Centrally-mediated anti nociceptive actions of GABAA receptor agonists in the rat spared nerve injury model of neuropathic pain. Eur.J.Pharmacol. 2005, 516:131–138.
[61] Vaught,J.L.,Pelley,K.,Costa,L.G.,Settler,P.,andEnna,S.J.A comparison of the antino ciceptive responses to the GABA receptor agonists THIP and baclofen. Neuropha rmacology. 1985, 24: 211–216.
[62] Zorn,S.H.,and Enna,S.J..The effect of mouse spinal cord transaction on the antinociceptive response to gamma-amino butyric acid agonistsTHIP (4,5,6,-tetrahy-droi -soxazolo[5,4-c]pyridine-3-ol) and baclofen. BrainRes.1985b, 338:380–383.
[63] Zorn,S.H.,andEnna,S.J. The GABA agonist THIP attenuates antinociception in the mo–use by modifying central cholinergic transmission. Neuropharmacology. 1987, 26, 433–437.
[64] Green,G.M.,andDickenson,A.GABA-receptor control of the amplitude and duration of the neuronal responses to formalin in the rat spinalcord. Eur.J.Pain 1997, 1: 95–104.
[65] Kaneko,M.,andHammond,D.L.Role of spinal gamma-amino butyric acid A receptors Inf -ormalin-induced nociception in the rat. J.Pharmacol.Exp.Ther. 1997. 282: 928–938.
[66] Hwang,J.H.,andYaksh,T.L.The effect of spinal GABA receptor agonists on tactile allod -ynia in a surgically-induced neuropathic pain mode lin the rat. Pain1987, 70:15–22.
[67] Loomis,C.W.,Khandwala,H.,Osmond,G.,andHefferan,M.P..Co-administration of Intra thecal strychnine and bicuculline effects synergistic allodynia in the rat:An Isobolo graphic analysis. J.Pharmacol.Exp.Ther. 2001,296:756–761.
[68] Eaton,M.J.,Martinez,M.A.,andKarmally,S.A single intrathecal injection of GABA Perma -nently reverses neuropathic pain after nerve injury. BrainRes. 1999, 835: 334–339.
[69] Liu W, Liu Z, Liu L, Xiao Z, Cao X, Cao Z, Xue L, Miao L, He X, Li W.A novel human foamy virus mediated gene transfer of GAD67 reduces neuropathic pain following spinal cord injury. Neurosci Lett. 2008, 432(1):13-8.
[70] Lee JY, Fink DJ, Mata M. Vector-mediated gene transfer to express inhibitory neurotransmitters in dorsal root ganglion reduces pain in a rodent model of lumbar radiculopathy. Spine. 2006, 31(14):1555-8.
[71] Kanai A, Sarantopoulos C, McCallum JB, Hogan Q. Painful neuropathy alters the effect of gabapentin on sensory neuron excitability in rats. Acta Anaesthesiol Scand. 2004 , 48(4):507-12.
[72] Ugarte,S.D.,Homanics,G.E.,Firestone,L.L.,and Hammond,D.L.Sensory thresholds and the antinociceptive effects of GABA receptor agonists in mice lacking the b3 subunit of the GABAA receptor. Neuroscience 1999, 95:795–806.
[73] Zheng,W.,Xie,W.,Zhang,J.,Strong,J.A.,Wang,L.,Yu,L.,Xu,M.,andLu,L.Function ofγ-amino butyric acid receptor/channelγ1-subunits in spinal cord. J.Biol.Chem. 2003, 278: 48321–48329.
[74] Obata K, Yamanaka H, Fukuoka T, Yi D, Tokunaga A, Hashimoto N, Yoshikawa H, Noguchi K. Contribution of injured and uninjured dorsal root ganglion neurons to pain behavior and the changes in gene expression following chronic constriction injury of the sciatic nerve in rats. Pain. 2003 ,101(1-2):65-77.
[75] Zhang X, Xiao HS. Gene array analysis to determine the components of neuropathic pain signaling.Curr Opin Mol Ther. 2005, 7(6):532-7.
[76] Xiao HS, Huang QH, Zhang FX, Bao L, Lu YJ, Guo C, Yang L, Huang WJ, Fu G, Xu SH, Cheng XP, Yan Q, Zhu ZD, Zhang X, Chen Z, Han ZG, Zhang X.Identification of gene expression profile of dorsal root ganglion in the rat peripheral axotomy model of neuropathic pain. Proc Natl Acad Sci U S A. 2002, 99(12):8360-5.
[77]潘阳杏,谢作磊,曹慧仁,吴燕婉,谢益宽.慢性痛大鼠背根神经元基因表达的研究.中国神经免疫学和神经病学杂志. 2006,13(3): 144-149
[78] Moss, S. J., Doherty, C. A., and Huganir, R. L. Identification of the cAMP-dependent protein kinase and protein kinase C phosphorylation sites within the major intracellular domains of the beta 1, gamma 2S, and gamma 2L subunits of the gamma-aminobutyric acid type A receptor. J. Biol. Chem. 1992,267:14470–14476.
[79] Moss, S. J., Smart, T. G., Blackstone, C. D., and Huganir, R. L. Functional modulation of GABAA receptors by cAMP-dependent protein phosphorylation. Science, 1992, 257: 661–665.
[80] Krishek, B. J., Xie, X., Blackstone, C. D., Huganir, R. L., Moss, S. J., and Smart, T. G. Neuron,1994,12: 1081–1095.
[81] McDonald, B. J., and Moss, S. J. Conserved phosphorylation of the intracellular domains of GABA(A) receptor beta2 and beta3 subunits by cAMP-dependent protein kinase, cGMP-dependent protein kinase protein kinase C and Ca2+/calmodulin type II-dependent protein kinase. Neuropharmacology,1997, 36: 1377–1385.
[82] C.R. Marutha Ravindran, Maharaj K. Ticku.Tyrosine kinase phosphorylation of GABAA receptor subunits following chronic ethanol exposure of cultured cortical neurons of mice. Brain research, 2006,1086:35-41.
[83] Huang, R.Q., Dillon, G.H.,. Maintenance of recombinant type Aγ-aminobutyric acid receptor function: role of protein tyrosine phosphorylation and calcineurin. J. Pharmacol. Exp. Ther. 1998,286: 243–255.
[84] Yang L, Zhang FX, Huang F, Lu YJ, Li GD, Bao L, Xiao HS, Zhang X. Peripheral nerve injury induces transsynaptic modification of channels, receptors and signal pathways in rat dorsal spinal cord. Eur J Neurosci 2004;19:871–883.
[85] CastroLopes JM, Malcangio M, Pan BH, Bowery NG. Complex changes of GABAA and GABAB receptor binding in the spinal cord dorsal horn following peripheral inflammation or neurectomy. Brain Res 1995;679:289–297.
[86] Xiao HS, Huang QH, Zhang FX, Bao L, Lu YJ, Guo C, Yang L, Huang WJ, Fu G, Xu SH, Cheng XP, Yan Q, Zhu ZD, Zhang X, Chen Z, Han ZG, Zhang X. Identification of gene expression profile of dorsal root ganglion in the rat peripheral axotomy model of neuropathic pain. Proc Natl Acad Sci USA 2002;99:8360–8365.
[87] Mitchel P. Engle, Martin Gassman, Kenneth T. Sykes, Bernhard Bettler, and Donna L. Hammond1. Spinal Nerve Ligation Does Not Alter the Expression or Function of GABAB Receptors in Spinal Cord and Dorsal Root Ganglia of the Rat. Neuroscience. 2006 ; 138(4): 1277–1287.
[88] Hiroshi Ueda. Peripheral mechanisms of neuropathic pain-involvement of lysophos -phatidic acid receptor-mediated demylination. Molecular pain. 2008,4(11):1-13
[1] KRARUP C an update on electrophysiological studies in neuropathy. Curr Opin Neurol. 2003,16:603-612.
[2] Miller,RJ: Multiple calcium channels and neuronal function. Science. 1987,235:46-52
[3] Perez-Reyes,E. Molecular physiology of low-voltage activated t-type calcium channels.Physiol.rev. 2003, 83:117-161.
[4] Tsien, R.W.,Ellinor,P.T.,and Horne, W.A.Molecular diversity of voltage-dependent Ca2+ channels.Trends Pharmacol. Sci. 1999,12:349-354.
[5] Westenbroek RE,Hoskins L,Catterall WA: localization of Ca2+ channel subtypes on rat spinal motor neurons, interneurons and nerve terminal. J Neurosci. 1998, 18: 6319 -6330.
[6] Scroggs RS,Fox AP: Calcium current variation between acutely isolated adult rat dorsal root ganglion neurons of different size. J Physiol. 1992,445:639-658.
[7] Bell TJ,Thaler C,Castiglioni AJ. Cell-specific alternative splicing increases calcium channel current density in the pain pathway.Neuron, 2004, 41:121-138.
[8] Cizkova D, Marsala J,Lukacova N, Marsala M, Jergovas, Orendacova J, Yaksh TL: Localization of N-type Ca2+ channels in the rat spinal cord following chronic constricitve nerve injury. Exp Brain Res. 2002, 147:456-463.
[9]文磊,杨胜,周文霞等.N型钙通道与疼痛.生理科学进展, ,2005, 36(1):23-28.
[10]Maeno-Hikichi Y, Chang S, Matsumura K, et al. A PKC epsilon-ENH-channel complex specifically modulates N-tpye Ca2+ channels. Nat Neurosci.2003,6:468-475.
[11]Beuckmann CT, Sinton CM, Miyamoo. N,et al. N-type calcium channelα1βsubunit Cav2.2 knockout mice display hyperactivity and vigilance state differences. J Neuros -ci. 2003.23:6793-6797.
[12]Terlau H,Olivera BM. Conus Venoms: a rich source of novel ion channel targeted peptides.Physiol Rev. 2004, 84:41-68.
[13]Doggrell SA: Intrathecal zicontide for refractory pain. Expert Opin Ivesting Drugs 2004, 13:875-877.
[14]Takahara, A. et al. Antisympathetic and hemodynamic property of a dual L/N-type Ca2+ channel blocker cilnidipine in rats. Eur. J. Pharmacol. 2002,434: 43–47.
[15]Lewis, R.J. et al.Novel omega-conotoxins from Conus catus discriminate among neuronal calcium channel subtypes. J. Biol. Chem. 2002,275: 35335–35344.
[16]Evans AR,Nicol GD,Vasko MR:differential regulation of evoked peptide release by voltage-sensitve calcium channels in rat sensory neurons.Brain Res.1996, 712 : 265 -273.
[17]Kraus RL,Sinnegger MJ,Koschak A,Glossmann H,Stenirri S,Carrera P,Striessnig J: Three new familial hemiplegic migraine mutants affect P/Q type Ca2+ channel kinetics. J Bio Chem. 2000, 275:9239-9243.
[18]Heinke B,Balzer E,Sardkuhler J:Pre-and postsynaptic contributions of voltage -dependent Ca2+ channels to noceptive transmission in rat spinal lamina I neurons. Eur J neurosci 2004,19:103-111.
[19]Fukuizumi T, Ohkubo T, kitamurak: Spinal sensitization mechanism in vincri -stine-induced hyperalgesia in mice. Neurosci lett. 2003,343:89-92.
[20]Murakami M, Nakagawasai O, Suzuki T, et al. Antinociceptive effect of different types of calcium channel inhibitors and the distribution of various calcium channel alpha 1 subunits in the dorsal horn of spinal cord in mice. Brain Res. 2004, 1024 (1–2):122–129.
[21]Isope P,Murphy TH.Lowthreshold calcium currents in rat cerebellar purkinje cell dendritic spines are mediated by T-type calcium channels.J physio, 2005, 562 (ptl) :257-269.
[22]Talley EM, Cribbs LL, Lee JH, Daud A, Perez-Reyes E, Bayliss DA: Differential distribution of three members of a gene family encoding low voltage-activated (T-type)calcium channels. J Neurosci. 1999,19:1895-1911.
[23]Yusaf SP, Goodman J, Pinnock RD, Dixon AK, Lee K: Expression of voltage-gated calcium channel subunits in rat dorsal root ganglion neurons. Neurosci Lett. 2001, 311:137-141.
[24]Perez-Reyes E: Molecular physiology of low-voltageactivated t-type calcium channels. Physiol Rev. 2003,83:117-161.
[25]Ikeda H, Heinke B, Ruscheweyh R, Sandkuhler J: Synaptic plasticity in spinal lamina I projection neurons that mediate hyperalgesia. Science. 2003,299:1237-1240.
[26]McCallum, J.B. et al. Loss of T-type calcium current in sensory neurons of rats with neuropathic pain. Anesthesiology. 2003,98:209–216.
[27]Bourinet, E. et al. Silencing of the Cav3.2 T-type calcium channel gene in sensory neurons demonstrates its major role in nociception. EMBO J. 2005,24:315–324.
[28]Herrero, J.F. et al. Wind-up of spinal cord neurones and pain sensation: much ado about something? Prog. Neurobiol. 2000,61:169–203.
[29]Joksovic, P.M. et al.Different kinetic properties of two T-type Ca2+ currents of rat reticular thalamic neurones and their modulation by enflurane. J. Physiol. 2005,566: 125–142.
[30]Kim DS, Yoon CH, Lee SJ, Park SY, Yoo HJ, Cho HJ: Changes in voltage-gated calcium channel alpha(1) gene expression in rat dorsal root ganglia following peripheral nerve injury. Brain Res Mol Brain Res. 2001, 96:151-156.
[31]Evans AR, Nicol GD, Vasko MR: Differential regulation of evoked peptide release by voltage-sensitive calcium channels in rat sensory neurons. Brain Res. 1996, 712: 265 -273.
[32]Chaplan SR, Pogrel JW, Yaksh TL. Role of voltage-dependent calcium channel subtypes in experimental tactile allodynia. J Pharmacol Exp Ther. 1994, 269 (3): 1117–1123.
[33]Gupta M, Singh J, Sood S, Arora B: Mechanism of antinociceptive effect of nimodipine in experimental diabetic neuropathic pain. Methods Find Exp Clin Pharmacol. 2003, 5:49-52.
[34]Yang L, Zhang FX, Huang F, Lu YJ, Li GD, Bao L, Xiao HS, Zhang X: Peripheral nerve injury induces trans-synaptic modification of channels, receptors and signal pathways in rat dorsal spinal cord. Eur J Neurosci. 2004,19:871-883.
[35]Luo ZD, Chaplan SR, Higuera ES, Sorkin LS, Stauderman KA, Williams ME, Yaksh TL: Upregulation of dorsal root ganglion {alpha}2{delta} calcium channel subunit and its correlation with allodynia in spinal nerve-injured rats. J Neurosci. 2001,21:1868-1875.
[36]Mould J, Yasuda T, Schroeder CI, Beedle AM, Doering CJ, Zamponi GW, Adams DJ, Lewis RJ: The alpha2delta auxiliarysubunit reduces affinity of omega-conotoxins for recombinant N-type (Cav2.2) calcium channels. J Biol Chem. 2004,279:34705-34714.
[37]Sutton KG,Martin DJ,Pinnock RD,Leek,Scott RH: Gapapentin inhibits high-threshod calcium channel currents in cultured rat dorsal root ganglion neurons.Br J pharmacol . 2002,135:257-265.
[38]Amin B, Hee, KK, Yeoung SL, Doosikk; Injured discharges regulate calcium channel {alpha}2{delta}1 subunit upregulation in the dorsal horn that contributes to initiationof neuropathic pain. Pain. 2008,139:358-366.