大鼠实验性牙移动中P2X_3受体在Vc的表达变化研究
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摘要
正畸治疗是通过对错位的牙、牙弓或颌骨施加一定的矫治力来达到畸形矫治的目的。伴随着机体的诸多反应，疼痛的产生是正畸治疗中最常见和最棘手的问题。
细胞外三磷酸腺苷(ATP)已经被证实是组织中伤害性刺激(包括疼痛)传导的重要神经递质，ATP与其受体P2X_3结合后传递疼痛信息。P2X_3受体是嘌呤受体P2X家族的一员。在背根神经节的小细胞上有P2X_3受体的选择性表达，P2X_3受体阳性的神经元轴突中枢端投射到脊髓背角Ⅱ层内侧部，外周端投射到皮肤和内脏；在三叉神经节上，P2X_3受体分布在中小型神经元细胞上，其中枢端投射到三叉神经脊束核尾侧亚核(Vc)，外周端投射到牙槽和舌的环状乳头。另外在交感颈上神经节和腹腔神经节也有P2X_3受体的少量表达。口面部的伤害性信息是由三叉神经传导，目前已经确认，三叉神经脊束核尾侧亚核(Vc)是口面部疼痛信息由外周传入中枢的第一门户。
当正畸加力使牙移动时，由于牙周膜、牙槽骨和牙龈等会发生组织改建，将对神经有激惹并造成一定的神经损伤，可能使细胞内的ATP向细胞外流动，从而导致患者出现疼痛不适等感觉异常。动物实验也证实，实验性牙移动导致的三叉神经节内P2X_3受体的表达变化与临床上患者的疼痛周期基本一致，提示P2X_3受体在正畸疼痛中可能发挥了重要的作用。但是目前在牙移动过程中，P2X_3受体在三叉神经脊束核尾侧亚核(Vc)的表达变化的相关研究国内外均未见报道。
本实验将43只SD大鼠分为空白组(4只)，对照组(4只)，实验组(35只)。空白组的大鼠直接断颈处死；对照组大鼠麻醉后进行与实验组相同的实验过程但不加力，即刻处死；实验组大鼠麻醉后在左侧安放加力装置，于4小时、12小时、24小时、2天、3天、5天、7天分别处死5只实验组大鼠。分别取出各组大鼠的延髓定位Vc后冰冻切片，应用免疫组织化学的方法研究P2X_3受体在三叉神经脊束核尾侧亚核(中枢)的表达变化，目的在于探索正畸牙移动中加力后P2X_3受体在中枢的变化规律，并与其在三叉神经节(外周)的表达规律进行比较，为明确正畸牙移动疼痛机理以及将来进一步研究P2X_3受体拮抗剂治疗正畸疼痛提供实验依据。
实验结果显示：
1、大鼠Vc中存在少量的P2X_3受体，以浅层居多，通过牙移动实验使大鼠牙受力移动后，加力侧P2X_3受体免疫阳性反应增加，并呈现一定的时间规律：受力后4小时即出现明显变化，实验后3天时达到高峰，然后逐渐下降至第7天。
2、未加力侧的P2X_3受体免疫阳性反应在大鼠牙受力移动的7天内也发生了明显的变化，其变化趋势与加力侧略有不同：受力12小时后出现明显的变化，而高峰值出现在第5天，然后逐渐下降至第7天。
3、大鼠加力侧的P2X_3受体免疫阳性反应水平与同时间点的未加力侧相比有明显差异，加力侧的免疫反应强于未加力侧。
4、将本实验结果与前期研究(大鼠实验性牙齿移动中三叉神经节P2X_3受体表达变化的研究—曹阳)比较得出：正畸牙移动中加力后P2X_3受体在三叉神经脊束核尾侧亚核(中枢)的表达变化规律与其在三叉神经节(外周)的表达规律基本相同，而非加力侧的表达变化较前二者稍有推后(或延迟)。
综上所述，在大鼠的牙移动过程中，Vc中加力侧的P2X_3受体表达变化呈现短时上调的规律，其与外周的表达规律基本相同，表明P2X_3受体在外周与中枢都与牙移动伤害表达及传递密切相关；而未加力侧的P2X_3受体免疫阳性反应也呈现相似的规律，表明三叉神经纤维对中枢的投射可能在Vc处有交叉至对侧，对侧的反应略晚于加力侧。其作用机制及向上级中枢的传导还有待进一步探索。
Pain is one of the most troublesome and commonest problems encountered by orthodontists clinically. More and more researches have been focusing on this field. Considerable evidences have indicated that Adenosine Triphosphate (ATP) has played a crucial role in pain transmission as a possible neurotransmitter. P2X_3 receptor is one of ATP receptors, which was found to be attributed to pain transmission. Formerly studies in our team have suggested that P2X_3 receptor may be involved in orthodontic pain, which merely pay attention to periphery nerve system, however, spinal trigeminal subnucleus caudalis (Vc) has been found to be related to oral facial pain closely, which was considered as a part of central nervous system (CNS). Therefore, present research mainly investigated the P2X_3 receptor changes in Vc during experimental tooth movement in rat at early stage.
43 male SD rats (200-250g) were selected for this research. There were 7 experimental groups (4h, 12h, 24h, d2, d3, d5, d7) and 2 control groups [Group A: intact rat ; Group B: rat received false experimental tooth movement].5 rats were involved in each experimental group and 4 rats were contained in each control group. 80g force was applied to upper left incisor and the first left molar using close Ni-Ti coil. Immunohistology was used to reveal the distribution of P2X_3 receptors in Vc.
Results showed as follows:
1. P2X_3 receptor staining was found in Vc, which was expressed in superficial layer of Vc dominantly. Predominant up regulation of P2X_3 receptor immunoactivity was found on the left side (ipsilateral) from 4h to 7 day. It started to significantly increase at 4h, peaked at 3 day, then decreased continuously, as compared with the Group B. This kind of rhythm change was similar to initial orthodontic pain responses investigated in clinical.
2. The rhythm change of P2X_3 receptor staining was also found in Vc on the right side (Contralateral) during the 7 days long period when compared with Group B. It was interesting to find that P2X_3 receptor staining started to increase significantly at 12h, peaked on 5 day, then decreased constantly.
3. Significant difference was found when compared the immunoactivity of P2X_3 receptor between the left and right side in Vc. The experimental side (left) showed significant increased immune positive neurons than that of the control side (right).
4. As compared with former study of our team, which investigated the P2X_3 receptors changes in trigeminal ganglion (TG) after experimental tooth movement in rat at early stage, similar changes were found between the two individual studies.
On the whole, P2X_3 receptor had a rhythm change in Vc of rat as a result of experimental tooth movement on ipsilateral side and contra lateral side, which was similar to the result in TG (periphery nerve system). Also, the rhythm change was almost correspondent to the pain response after the first arch wires were ligatured at the early stage clinically. Thus, P2X_3 receptor may play an important role in orthodontic pain. Furthermore, the change of P2X_3 receptor on the Contralateral side may reveal that nerve fibers of trigeminal ganglion may project to the contra lateral side in Vc limitedly. However, the delayed response of P2X_3 receptor after experimental tooth movement on contra lateral side should be further investigated. Meanwhile, more attention should be paid to the P2X_3 receptor in superdorasl nerve system.
细胞外三磷酸腺苷(ATP)已经被证实是组织中伤害性刺激(包括疼痛)传导的重要神经递质，ATP与其受体P2X_3结合后传递疼痛信息。P2X_3受体是嘌呤受体P2X家族的一员。在背根神经节的小细胞上有P2X_3受体的选择性表达，P2X_3受体阳性的神经元轴突中枢端投射到脊髓背角Ⅱ层内侧部，外周端投射到皮肤和内脏；在三叉神经节上，P2X_3受体分布在中小型神经元细胞上，其中枢端投射到三叉神经脊束核尾侧亚核(Vc)，外周端投射到牙槽和舌的环状乳头。另外在交感颈上神经节和腹腔神经节也有P2X_3受体的少量表达。口面部的伤害性信息是由三叉神经传导，目前已经确认，三叉神经脊束核尾侧亚核(Vc)是口面部疼痛信息由外周传入中枢的第一门户。
当正畸加力使牙移动时，由于牙周膜、牙槽骨和牙龈等会发生组织改建，将对神经有激惹并造成一定的神经损伤，可能使细胞内的ATP向细胞外流动，从而导致患者出现疼痛不适等感觉异常。动物实验也证实，实验性牙移动导致的三叉神经节内P2X_3受体的表达变化与临床上患者的疼痛周期基本一致，提示P2X_3受体在正畸疼痛中可能发挥了重要的作用。但是目前在牙移动过程中，P2X_3受体在三叉神经脊束核尾侧亚核(Vc)的表达变化的相关研究国内外均未见报道。
本实验将43只SD大鼠分为空白组(4只)，对照组(4只)，实验组(35只)。空白组的大鼠直接断颈处死；对照组大鼠麻醉后进行与实验组相同的实验过程但不加力，即刻处死；实验组大鼠麻醉后在左侧安放加力装置，于4小时、12小时、24小时、2天、3天、5天、7天分别处死5只实验组大鼠。分别取出各组大鼠的延髓定位Vc后冰冻切片，应用免疫组织化学的方法研究P2X_3受体在三叉神经脊束核尾侧亚核(中枢)的表达变化，目的在于探索正畸牙移动中加力后P2X_3受体在中枢的变化规律，并与其在三叉神经节(外周)的表达规律进行比较，为明确正畸牙移动疼痛机理以及将来进一步研究P2X_3受体拮抗剂治疗正畸疼痛提供实验依据。
实验结果显示：
1、大鼠Vc中存在少量的P2X_3受体，以浅层居多，通过牙移动实验使大鼠牙受力移动后，加力侧P2X_3受体免疫阳性反应增加，并呈现一定的时间规律：受力后4小时即出现明显变化，实验后3天时达到高峰，然后逐渐下降至第7天。
2、未加力侧的P2X_3受体免疫阳性反应在大鼠牙受力移动的7天内也发生了明显的变化，其变化趋势与加力侧略有不同：受力12小时后出现明显的变化，而高峰值出现在第5天，然后逐渐下降至第7天。
3、大鼠加力侧的P2X_3受体免疫阳性反应水平与同时间点的未加力侧相比有明显差异，加力侧的免疫反应强于未加力侧。
4、将本实验结果与前期研究(大鼠实验性牙齿移动中三叉神经节P2X_3受体表达变化的研究—曹阳)比较得出：正畸牙移动中加力后P2X_3受体在三叉神经脊束核尾侧亚核(中枢)的表达变化规律与其在三叉神经节(外周)的表达规律基本相同，而非加力侧的表达变化较前二者稍有推后(或延迟)。
综上所述，在大鼠的牙移动过程中，Vc中加力侧的P2X_3受体表达变化呈现短时上调的规律，其与外周的表达规律基本相同，表明P2X_3受体在外周与中枢都与牙移动伤害表达及传递密切相关；而未加力侧的P2X_3受体免疫阳性反应也呈现相似的规律，表明三叉神经纤维对中枢的投射可能在Vc处有交叉至对侧，对侧的反应略晚于加力侧。其作用机制及向上级中枢的传导还有待进一步探索。
Pain is one of the most troublesome and commonest problems encountered by orthodontists clinically. More and more researches have been focusing on this field. Considerable evidences have indicated that Adenosine Triphosphate (ATP) has played a crucial role in pain transmission as a possible neurotransmitter. P2X_3 receptor is one of ATP receptors, which was found to be attributed to pain transmission. Formerly studies in our team have suggested that P2X_3 receptor may be involved in orthodontic pain, which merely pay attention to periphery nerve system, however, spinal trigeminal subnucleus caudalis (Vc) has been found to be related to oral facial pain closely, which was considered as a part of central nervous system (CNS). Therefore, present research mainly investigated the P2X_3 receptor changes in Vc during experimental tooth movement in rat at early stage.
43 male SD rats (200-250g) were selected for this research. There were 7 experimental groups (4h, 12h, 24h, d2, d3, d5, d7) and 2 control groups [Group A: intact rat ; Group B: rat received false experimental tooth movement].5 rats were involved in each experimental group and 4 rats were contained in each control group. 80g force was applied to upper left incisor and the first left molar using close Ni-Ti coil. Immunohistology was used to reveal the distribution of P2X_3 receptors in Vc.
Results showed as follows:
1. P2X_3 receptor staining was found in Vc, which was expressed in superficial layer of Vc dominantly. Predominant up regulation of P2X_3 receptor immunoactivity was found on the left side (ipsilateral) from 4h to 7 day. It started to significantly increase at 4h, peaked at 3 day, then decreased continuously, as compared with the Group B. This kind of rhythm change was similar to initial orthodontic pain responses investigated in clinical.
2. The rhythm change of P2X_3 receptor staining was also found in Vc on the right side (Contralateral) during the 7 days long period when compared with Group B. It was interesting to find that P2X_3 receptor staining started to increase significantly at 12h, peaked on 5 day, then decreased constantly.
3. Significant difference was found when compared the immunoactivity of P2X_3 receptor between the left and right side in Vc. The experimental side (left) showed significant increased immune positive neurons than that of the control side (right).
4. As compared with former study of our team, which investigated the P2X_3 receptors changes in trigeminal ganglion (TG) after experimental tooth movement in rat at early stage, similar changes were found between the two individual studies.
On the whole, P2X_3 receptor had a rhythm change in Vc of rat as a result of experimental tooth movement on ipsilateral side and contra lateral side, which was similar to the result in TG (periphery nerve system). Also, the rhythm change was almost correspondent to the pain response after the first arch wires were ligatured at the early stage clinically. Thus, P2X_3 receptor may play an important role in orthodontic pain. Furthermore, the change of P2X_3 receptor on the Contralateral side may reveal that nerve fibers of trigeminal ganglion may project to the contra lateral side in Vc limitedly. However, the delayed response of P2X_3 receptor after experimental tooth movement on contra lateral side should be further investigated. Meanwhile, more attention should be paid to the P2X_3 receptor in superdorasl nerve system.
引文
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1. Wall P, Melzack R: Textbook of pain.3rd ed. Edinburgh Churchill Livingstone 1994, 236-359.
2. LaMotte.RH, Campbell.JN: Comparison of responses of warm and nociceptive C-fiber afferents in monkey with human judgments of thermal pain. Journal of Neurophysiology, 1978, 41(2):509-28.
3．韩济生：神经科学纲要(M)．2版．北京：北京医科大学北京协和医科大学联合出版社1999，706-725．
4. Wei F, Xia X, Tang J: Calmodulin regulates synaptic plasticity in the anterior cingulate cortex and behavioral responses:a microelectroporation study in adult rodents. J Neurosci 2003, 23(23): 8402-8409.
5. Gebhart G: Modulatory effect of descending systems on spinal dorsal horn neurons. Spinal Afferent Process 1986, 15(4): 391-426.
6. Turner.DF, Marfurt.CF: Uptake and transneuronal transport of horseradish peroxidase-wheat germ agglutinin by tooth pulp primary affernt neurons. Brain Research 1988, 452:381-387
7．王智明，李云庆，施际武：大鼠Vc内SP受体阳性神经元、FOS阳性神经元及初级传入C纤维和终末分布的研究．神经解剖学杂志1996，12(1)：15—20．
8. Bereiter.DA, Benetti.AP: Excitatory amino release within spinal trigeminal nucleus after mustard oil injection into the temporomandibular joint region of the rat. Pain 1996, 67(2-3): 451-459.
9. Tsai.CM, Chiang.CY, Yu.XM, Sessle.BJ: Involvement of trigeminal subnucleus caudalis(medullary dorsal horn)in craniofacial nociceptive reflexactivity. Pain 1999, 81(1-2): 115-128.
10. Drury.AN, Szent.GA: The physiological activity of adenine compounds with especial reference to their action upon the mammalian heart. J Physiol 1929, 68: 213-237.
11. Gillespie.JH: The biological significance of the linkages in adenosine triphosphoric acid. J Physiol 1934, 80: 345-349.
12. Holton.P: The liberation of adenosine triphosphate on antidromic stimulation of sensory nerves. J Physiol 1959, 145: 494-504.
13. Burnstock.G, Campbell.G; Satchell.D: Evidence that adenosine triphosphate or a related nucleotide is the transmitter substance released by non-sdrenergic inhibitory nerves in the gut. Br J Pharmacol 1970, 40: 668-688.
14. Bleehen.T, Hobbiger.F, Keele.CA: Indentification of algogenic substances in human erythrocytes. J Physiol 1976, 262: 131-149.
15. Chen.C: A P2X_3 purinoceptor expressed by a subset of sensory neurons. Nature 1995, 377(6548): 428-431.
16. Lewis.C: Coexpression of P2X_3 and P2X_3 receptor subunits can account for ATP-gated currents in sensory neurons. Nature 1995, 377(6548): 432-435.
17. Burnstock.G, Kennedy.C: Is there a basis for distinguishing two types of P2-purinoceptor?.. General Pharmacology 1985, 16(5): 433-440.
18. Kennedy.C, Leff.P: Painful connection for ATP. Nature 1995, 377: 385-386.
19. Souslova.V, Ravenall.S, Fox.M, Wells.D, Wood.JN, Akopian.AN: Structure and chromosomal mapping of the mouse P2X_3 gene. Gene 1997,195(1): 101-111.
20. Garcia-Guzman.M, Stuhmer.W, Soto.F: Molecular characterization and pharmacological properties of the human P2X_3 purinoceptor. . Brain Research. Molecular Brain Research 1997, 47(1-2): 59-66.
21. Nicke.A, Baumert.HG, Rettinger.J, et al.: P2X_1 and P2X_3 receptors form stable trimers: a novel structural motif of ligand-gated ion channels. EMBO Journal 1998,17(11): 3016-3028.
22. Cheung.K.K, Burnstock.G: Localization of P2X_3 receptors and coexpression with P2X_2 receptors during rat embryonic neurogenesis. Journal of Comparative Neurology 2002,443(4): 368-382.
23. Llewellyn-Smith.IJ, Burnstock.G: Ultrastructural localization of P2X_3 receptors in rat sensory neurons. Neuroreport 1998, 9(11): 2545-2550.
24. Zhong.Y, Dunn.PM, Xiang.Z, Bo.X, Burnstock.G: Pharmacological and molecular characterization of P2X receptors in rat pelvic ganglion neurons. British Journal of Pharmacology 1998,125(4): 771-781.
25. Brouns.I, Adriaensen.D, Burnstock.G, Timmermans.JP: Intraepithelial vagal sensory nerve terminals in rat pulmonary neuroepithelial bodies express P2X(3) receptors. American Journal of Respiratory Cell & Molecular Biology 2000, 23(1): 52-61.
26. Phillips.JK, McLean.AJ, Hill.CE: Receptors involved in nerve-mediated vasoconstriction in small arteries of the rat hepatic mesentery. British Journal of Pharmacology 1998,124(7): 1403-1412.
27. Yiangou.Y, Facer.P, Ford.A, et al.: Capsaicin receptor VR1 and ATP-gated ion channel P2X_3 in human urinary bladder. BJU International 2001, 87(9): 774-779.
28. Alavi.AM, Dubyak.GR, Burnstock.G: Immunohistochemical evidence for ATP receptors in human dental pulp. . Journal of Dental Research 2001, 80(2): 476-483.
29. Staikopoulos.V, Sessle.BJ, Furness.JB, Jennings.EA: Localization of P2X_2 and P2X_3 receptors in rat trigeminal ganglion neurons. Neuroscience 2007, 144(1): 208.
30. Afework.M, Burnstock.G: Distribution of P2X receptors in the rat adrenal gland. Cell & Tissue Research 1999, 298(3): 449-456.
31. Glass.R, Townsend-Nicholson.A, Burnstock.G: P2 receptors in the thymus: expression of P2X and P2Y receptors in adult rats, an immunohistochemical and in situ hybridisation study. Cell & Tissue Research 2000, 300(2): 295-306.
32. Glass.R, Burnstock.G: Immunohistochemical identification of cells expressing ATP-gated cation channels (P2X receptors) in the adult rat thyroid. Journal of Anatomy 2001,198(5): 569-579.
33. Vlaskovska.M, Kasakov.L, Rong.W, et al.: P2X_3 knock-out mice reveal a major sensory role for urothelially released ATP. Journal of Neuroscience 2001, 21(15): 5670-5677.
34. Lee.HY, Bardini.M, Burnstock.G: Distribution of P2X receptors in the urinary bladder and the ureter of the rat. Journal of Urology 2000, 163(6): 2002-2007.
35. Lee.HY, Bardini.M, Burnstock.G: P2X receptor immunoreactivity in the male genital organs of the rat. Cell & Tissue Research 2000, 300(2): 321-330.
36. Slater.M, Barden.JA, Murphy.CR: The purinergic calcium channels P2X_(1,2,5,7) are down-regulated while P2X_(3,4,6) are up-regulated during apoptosis in the ageing rat prostate. Histochemical Journal 2000, 32(9): 571-580.
37. Slater.NM, Barden.JA, Murphy.CR: Distributional changes of purinergic receptor subtypes (P2X 1.7) in uterine epithelial cells during early pregnancy. Histochemical Journal 2000, 32(6): 365-372.
38. Bogdanov. Y, Rubino.A, Burnstock.G: Characterisation of subtypes of the P2X and P2Y families of ATP receptors in the foetal human heart. Life Sciences 1998,62(8): 697-703.
39. Brandle.U, Zenner.HP, Ruppersberg.JP: Gene expression of P2X-receptors in the developing inner ear of the rat. Neuroscience Letters 1999, 273(2): 105-108.
40. Bo.X, Alavi.A, Xiang.Z, Oglesby.I, Ford.A, Burnstock.G: Localization of ATP-gated P2X_2 and P2X_3 receptor immunoreactive nerves in rat taste buds. Neuroreport 1999,10(5): 1107-1111.
41. Kataoka.S, Toyono.T, Seta.Y, Toyoshima.K: Expression of ATP-gated P2X_3 receptors in rat gustatory papillae and taste buds. Archives of Histology & Cytology 2006, 69(4): 281-288.
42. Brandle.U, Guenther.E, Irrle.C, Wheeler-Schilling.TH: Gene expression of the P2X receptors in the rat retina. Brain Research. Molecular Brain Research 1998, 59(2): 269-272.
43. Kidd.EJ, Miller.KJ, Sansum.AJ, Humphrey.PP: Evidence for P2X_3 receptors in the developing rat brain. Neuroscience 1998, 87(3): 533-539.
44. Diaz-Hernandez.M, Gomez-Villafuertes.R, Hernando.F, Pintor.J, Miras-Portugal.MT: Presence of different ATP receptors on rat midbrain single synaptic terminals. Involvement of the P2X(3) subunits. Neuroscience Letters 2001, 301(3): 159-162.
45. Yao.ST, Barden.JA, Lawrence.AJ: On the immunohistochemical distribution of ionotropic P2X receptors in the nucleus tractus solitarius of the rat. Neuroscience 2001,108(4): 673-685.
46. Xiang.Z, Bo.X, Burnstock.G: Localization of ATP-gated P2X receptor immunoreactivity in rat sensory and sympathetic ganglia. Neuroscience Letters 1998, 256(2): 105-108.
47. Cockayne.DA, Hamilton.SG, Zhu.QM, et al.: Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X_3-deficient mice. Nature 2000, 407(6807): 1011-1015.
48. Ueno.S, Tsuda.M, Iwanaga.T, Inoue.K: Cell type-specific ATP-activated responses in rat dorsal root ganglion neurons. British Journal of Pharmacology 1999, 126(2): 429-436.
49. Friel.DD: An ATP-sensitive conductance in single smooth muscle cells from the rat vas deferens. Journal of Physiology 1988,401: 361-380.
50. Benham.CD: ATP-activated channels gate calcium entry in single smooth muscle cells dissociated from rabbit ear artery. Journal of Physiology 1989, 419: 689-701.
51. Gu.JG, MacDermott.AB: Activation of ATP P2X receptors elicits glutamate release from sensory neuron synapses. Nature 1997, 389(6652): 749-753.
52. Sokolova.E, Nistri.A, Giniatullin.R: The ATP-mediated fast current of rat dorsal root ganglion neurons is a novel effector for GABA(B) receptor activation. Neuroscience Letters 2003, 338(3): 181-184.
53. Hugel.S, Schlichter.R: Presynaptic P2X receptors facilitate inhibitory GABAergic transmission between cultured rat spinal cord dorsal horn neurons. Journal of Neuroscience 2000, 20(6): 2121-2130.
54. Bardoni.R, Goldstein.PA, Lee.CJ, Gu.JG, MacDermott.AB: ATP P2X receptors mediate fast synaptic transmission in the dorsal horn of the rat spinal cord. Journal of Neuroscience 1997,17(14): 5297-5304.
55. Cook.SP, Vulchanova.L, Hargreaves.KM, Elde.R, McCleskey.EW: Distinct ATP receptors on pain-sensing and stretch-sensing neurons. Nature 1997, 387(6632): 505-508.
56. Hamilton.SG, Wade.A, McMahon.SB: The effects of inflammation and inflammatory mediators on nociceptive behaviour induced by ATP analogues in the rat. British Journal of Pharmacology 1999,126(1): 326-332.
57. Bradbury.EJ, Burnstock.G, McMahon.SB: The expression of P2X_3 purinoreceptors in sensory neurons: effects of axotomy and glial-derived neurotrophic factor. Molecular & Cellular Neurosciences 1998, 12(4-5): 256-268.
58. Eriksson.J, Bongenhielm.U, Kidd.E, Matthews.B, Fried.K: Distribution of P2X_3 receptors in the rat trigeminal ganglion after inferior alveolar nerve injury. Neuroscience Letters 1998,254(1): 37-40.
59. Novakovic.SD, Kassotakis.LC, Oglesby.IB, et al.: Immunocytochemical localization of P2X_3 purinoceptors in sensory neurons in naive rats and following neuropathic injury. Pain 1999, 80(1-2): 273-282.
60. Tsuda.M, Koizumi.S, Inoue.K: ATP receptors in pain. Nippon Yakurigaku Zasshi - Folia Pharmacologica Japonica 2000,116(6): 343-350.
61. Cockayne.DA, Hamilton.SG, Zhu.QM, Dunn.PM: Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X_3-deficient mice. Nature 2000, 407(6807): 1011-1015.
62. Souslova.V, Cesare.P, Ding.Y, Akopian.AN: Warm-coding deficits and aberrant inflammatory pain in mice lacking P2X_3 receptors. Nature 2000, 407(6807): 1015-1017.
63. Ramer.MS, Bradbury.EJ, McMahon.SB: Nerve growth factor induces P2X(3) expression in sensory neurons. Journal of Neurochemistry 2001, 77(3): 864-875.
64. Cao.Y, Lai.WL, Chen.YX: Differential regulation of P2X_3 mRNA expression in the rat trigeminal ganglion after experimental tooth movement. Sichuan da Xue Xue Bao. Yi Xue Ban/Journal of Sichuan University. Medical Science Edition 2006, 37(5): 742-744.
65. Fukui.M, Nakagawa. T, Minami.M, Satoh.M, Kaneko.S: Inhibitory role of supraspinal P2X_3/ P2X_(2/3) subtypes on nociception in rats. Molecular Pain 2006, 2: 19.
2．小川记雄：脑受体．北京医科大学中国协和医科大学联合出版社1997．
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9. Bleehen.T, Hobbiger.F, Keele.CA: Indentification of algogenic substances in human erythrocytes. J Physiol 1976, 262: 131-149.
10. Chen.C: A P2X_3 purinoceptor expressed by a subset of sensory neurons. Nature 1995, 377(6548): 428-431.
11. Lewis.C: Coexpression of P2X_3 and P2X_3 receptor subunits can account for ATP-gated currents in sensory neurons. Nature 1995, 377(6548): 432-435.
12. Bumstock.G, Kennedy.C: Is there a basis for distinguishing two types of P2-purinoceptor?.. General Pharmacology 1985, 16(5): 433-440.
13．樊成涛，孙应明，段银钟：正畸治疗中疼痛机制的研究进展．国外口腔医学分册2000，27(2)：83-85．
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17. Shirazi.M, Khosrowshahi.M, Dehpour.AR: The effect of chronic renal insufficiency on orthodontic tooth movement in rats. Angle Orthodontist 2001, 71 (6): 494-498.
18．杨美祥，丁寅，徐如生：正畸牙齿移动中IL-1β在骨质疏松大鼠牙周组织中的分布变化．华西口腔医学杂志2000，18(5)：314-316．
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21. Gillespie.JH: The biological significance of the linkages in adenosine triphosphoric acid. J Physiol 1934, 80: 345-349.
22. Holton.P: The liberation of adenosine triphosphate on antidromic stimulation of sensory nerves. J Physiol 1959, 145: 494-504.
23. Oury.C, Toth-Zsamboki.E, Geet.C V, et al.: A natural dominant negative P2X_1 receptor due to deletion of a single amino acid residue. Joumal of Biological Chemistry 2000, 275(30): 22611-22614.
24. Ding.S, Sachs.F: Inactivation of P2X_2 purinoceptors by divalent cations. Journal of Physiology 2000, 522(2): 199-214.
25. Friel.DD: An ATP-sensitive conductance in single smooth muscle cells from the rat vas deferens. Journal of Physiology 1988, 401: 361-380.
26. Benham.CD: ATP-activated channels gate calcium entry in single smooth muscle cells dissociated from rabbit ear artery. Journal of Physiology 1989, 419: 689-701.
27. Cook.SP, Vulchanova.L, Hargreaves.KM, Elde.R, McCleskey.EW: Distinct ATP receptors on pain-sensing and stretch-sensing neurons. Nature 1997, 387(6632): 505-508.
28. Gu.JG, MacDermott.AB: Activation of ATP P2X receptors elicits glutamate release from sensory neuron synapses. Nature 1997, 389(6652): 749-753.
29. Sokolova.E, Nistri.A, Giniatullin.R: The ATP-mediated fast current of rat dorsal root ganglion neurons is a novel effector for GABA(B) receptor activation. Neuroscience Letters 2003, 338(3): 181-184.
30. Hugel.S, Schlichter.R: Presynaptic P2X receptors facilitate inhibitory GABAergic transmission between cultured rat spinal cord dorsal horn neurons. Journal of Neuroscience 2000, 20(6): 2121-2130.
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39. Balam.TA, Yamashiro.T, Zheng.L, S MA, Fujiyoshi.Y, Takano-Yamamoto.T: Experimental tooth movement upregulates preproenkephalin mRNA in the rat trigeminal nucleus caudalis and oralis. Brain Research 2005, 1036(1-2): 196-201.
40. Eriksson.J, Bongenhielm.U, Kidd.E, Matthews.B, Fried.K: Distribution of P2X_3 receptors in the rat trigeminal ganglion after inferior alveolar nerve injury. Neuroscience Letters 1998,254(1): 37-40.
41. Novakovic.SD, Kassotakis.LC, Oglesby.IB, et al.: Immunocytochemical localization of P2X_3 purinoceptors in sensory neurons in naive rats and following neuropathic injury. Pain 1999, 80(1-2): 273-282.
42. Bradbury.EJ, Burnstock.G, McMahon.SB: The expression of P2X_3 purinoreceptors in sensory neurons: effects of axotomy and glial-derived neurotrophic factor. Molecular & Cellular Neurosciences 1998,12(4-5): 256-268.
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45. Fukui.M, Nakagawa.T, Minami.M, Satoh.M, Kaneko.S: Inhibitory role of supraspinal P2X_3/P2X_(2/3) subtypes on nociception in rats. Molecular Pain 2006, 2: 19.
46. Kennedy.C, Leff.P: Painful connection for ATP. Nature 1995, 377: 385-386.
47. Neumann.S, Doubell.TP, Leslie.T, Woolf.CJ: Inflammatory pain hypersensitivity mediated by phenotypic switch in myelinated primary sensory neurons. Nature 1996, 384(6607): 360-364.
48. Noguchi.K, Morita.Y, Kiyama.H, Ono.K, Tohyama.M: A noxious stimulus induces the preprotachykinin-A gene expression in the rat dorsal root ganglion: a quantitative study using in situ hybridization histochemistry. Brain Research 1988, 464(1): 31-35.
1. Wall P, Melzack R: Textbook of pain.3rd ed. Edinburgh Churchill Livingstone 1994, 236-359.
2. LaMotte.RH, Campbell.JN: Comparison of responses of warm and nociceptive C-fiber afferents in monkey with human judgments of thermal pain. Journal of Neurophysiology, 1978, 41(2):509-28.
3．韩济生：神经科学纲要(M)．2版．北京：北京医科大学北京协和医科大学联合出版社1999，706-725．
4. Wei F, Xia X, Tang J: Calmodulin regulates synaptic plasticity in the anterior cingulate cortex and behavioral responses:a microelectroporation study in adult rodents. J Neurosci 2003, 23(23): 8402-8409.
5. Gebhart G: Modulatory effect of descending systems on spinal dorsal horn neurons. Spinal Afferent Process 1986, 15(4): 391-426.
6. Turner.DF, Marfurt.CF: Uptake and transneuronal transport of horseradish peroxidase-wheat germ agglutinin by tooth pulp primary affernt neurons. Brain Research 1988, 452:381-387
7．王智明，李云庆，施际武：大鼠Vc内SP受体阳性神经元、FOS阳性神经元及初级传入C纤维和终末分布的研究．神经解剖学杂志1996，12(1)：15—20．
8. Bereiter.DA, Benetti.AP: Excitatory amino release within spinal trigeminal nucleus after mustard oil injection into the temporomandibular joint region of the rat. Pain 1996, 67(2-3): 451-459.
9. Tsai.CM, Chiang.CY, Yu.XM, Sessle.BJ: Involvement of trigeminal subnucleus caudalis(medullary dorsal horn)in craniofacial nociceptive reflexactivity. Pain 1999, 81(1-2): 115-128.
10. Drury.AN, Szent.GA: The physiological activity of adenine compounds with especial reference to their action upon the mammalian heart. J Physiol 1929, 68: 213-237.
11. Gillespie.JH: The biological significance of the linkages in adenosine triphosphoric acid. J Physiol 1934, 80: 345-349.
12. Holton.P: The liberation of adenosine triphosphate on antidromic stimulation of sensory nerves. J Physiol 1959, 145: 494-504.
13. Burnstock.G, Campbell.G; Satchell.D: Evidence that adenosine triphosphate or a related nucleotide is the transmitter substance released by non-sdrenergic inhibitory nerves in the gut. Br J Pharmacol 1970, 40: 668-688.
14. Bleehen.T, Hobbiger.F, Keele.CA: Indentification of algogenic substances in human erythrocytes. J Physiol 1976, 262: 131-149.
15. Chen.C: A P2X_3 purinoceptor expressed by a subset of sensory neurons. Nature 1995, 377(6548): 428-431.
16. Lewis.C: Coexpression of P2X_3 and P2X_3 receptor subunits can account for ATP-gated currents in sensory neurons. Nature 1995, 377(6548): 432-435.
17. Burnstock.G, Kennedy.C: Is there a basis for distinguishing two types of P2-purinoceptor?.. General Pharmacology 1985, 16(5): 433-440.
18. Kennedy.C, Leff.P: Painful connection for ATP. Nature 1995, 377: 385-386.
19. Souslova.V, Ravenall.S, Fox.M, Wells.D, Wood.JN, Akopian.AN: Structure and chromosomal mapping of the mouse P2X_3 gene. Gene 1997,195(1): 101-111.
20. Garcia-Guzman.M, Stuhmer.W, Soto.F: Molecular characterization and pharmacological properties of the human P2X_3 purinoceptor. . Brain Research. Molecular Brain Research 1997, 47(1-2): 59-66.
21. Nicke.A, Baumert.HG, Rettinger.J, et al.: P2X_1 and P2X_3 receptors form stable trimers: a novel structural motif of ligand-gated ion channels. EMBO Journal 1998,17(11): 3016-3028.
22. Cheung.K.K, Burnstock.G: Localization of P2X_3 receptors and coexpression with P2X_2 receptors during rat embryonic neurogenesis. Journal of Comparative Neurology 2002,443(4): 368-382.
23. Llewellyn-Smith.IJ, Burnstock.G: Ultrastructural localization of P2X_3 receptors in rat sensory neurons. Neuroreport 1998, 9(11): 2545-2550.
24. Zhong.Y, Dunn.PM, Xiang.Z, Bo.X, Burnstock.G: Pharmacological and molecular characterization of P2X receptors in rat pelvic ganglion neurons. British Journal of Pharmacology 1998,125(4): 771-781.
25. Brouns.I, Adriaensen.D, Burnstock.G, Timmermans.JP: Intraepithelial vagal sensory nerve terminals in rat pulmonary neuroepithelial bodies express P2X(3) receptors. American Journal of Respiratory Cell & Molecular Biology 2000, 23(1): 52-61.
26. Phillips.JK, McLean.AJ, Hill.CE: Receptors involved in nerve-mediated vasoconstriction in small arteries of the rat hepatic mesentery. British Journal of Pharmacology 1998,124(7): 1403-1412.
27. Yiangou.Y, Facer.P, Ford.A, et al.: Capsaicin receptor VR1 and ATP-gated ion channel P2X_3 in human urinary bladder. BJU International 2001, 87(9): 774-779.
28. Alavi.AM, Dubyak.GR, Burnstock.G: Immunohistochemical evidence for ATP receptors in human dental pulp. . Journal of Dental Research 2001, 80(2): 476-483.
29. Staikopoulos.V, Sessle.BJ, Furness.JB, Jennings.EA: Localization of P2X_2 and P2X_3 receptors in rat trigeminal ganglion neurons. Neuroscience 2007, 144(1): 208.
30. Afework.M, Burnstock.G: Distribution of P2X receptors in the rat adrenal gland. Cell & Tissue Research 1999, 298(3): 449-456.
31. Glass.R, Townsend-Nicholson.A, Burnstock.G: P2 receptors in the thymus: expression of P2X and P2Y receptors in adult rats, an immunohistochemical and in situ hybridisation study. Cell & Tissue Research 2000, 300(2): 295-306.
32. Glass.R, Burnstock.G: Immunohistochemical identification of cells expressing ATP-gated cation channels (P2X receptors) in the adult rat thyroid. Journal of Anatomy 2001,198(5): 569-579.
33. Vlaskovska.M, Kasakov.L, Rong.W, et al.: P2X_3 knock-out mice reveal a major sensory role for urothelially released ATP. Journal of Neuroscience 2001, 21(15): 5670-5677.
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