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研究生:林家靖
研究生(外文):Chia-Ching Lin
論文名稱:物質P在酸誘發慢性肌肉疼痛中之止痛機制
論文名稱(外文):An Antinociceptive Role for Substance P in Acid-induced Chronic Muscle Pain
指導教授:陳志成陳志成引用關係
指導教授(外文):Chih-Cheng Chen
學位類別:博士
校院名稱:國立陽明大學
系所名稱:生化暨分子生物研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2011
畢業學年度:100
語文別:英文
論文頁數:116
中文關鍵詞:背根神經節物質P肌肉疼痛
外文關鍵詞:Dorsal Root GanglionSubstance PMuscle Pain
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物質P,一種結構為十一個胺基酸的神經胜肽,是重要的興奮性傳導分子, 過去研究顯示物質P對於疼痛感覺的形成相當重要。 在周邊組織釋放出來的物質P會造成血管通透度增加及血漿外渗,進而引發神經性炎症反應;但是分布在肌肉的末梢神經所釋放出來的物質P,並不會引發神經性炎症反應,也不會造成肌肉痛覺神經活化。目前為止物質P在肌肉疼痛中所扮演的角色還未被釐清.本篇研究利用神經細胞逆行性追蹤染劑,標記神經纖維延展到肌肉當中的背根神經節細胞(肌肉感覺神經元),再用全細胞膜片箝電生理記錄此群細胞活性。因為局部的組織酸化通常會造成肌肉疼痛,所以本論文首先研究物質P與酸所引發神經細胞活化的關連性。我發現分佈在肌肉感覺神經元中對酸最敏感的第三型酸敏性離子通道,其電流會被物質P所抑制。過去的研究曾顯示物質P會在不同區域的神經元中引發朝向細胞內的鈉離子流,造成細胞膜電位的去極化,進而提高神經元的活性。但在本篇研究當中,卻發現有相當高比例的肌肉痛覺神經元在物質P的刺激下都會引發向外電流,因此這些物質P所引發的向外電流會拮抗酸所引發的細胞膜電位去極化。相反地,由物質P刺激引發的向內電流在肌肉痛覺神經元中比例較少。本篇實驗進一步發現物質P所引發的向外電流是經由NK1受器,在不受G蛋白的調控下造成酪胺酸激酶的磷酸化,而酪胺酸激酶的磷酸化會打開M通道。M通道是一個電位控制型鉀離子通道,在調節細胞膜電位上扮演著重要的角色,其所造成的向外電流會使得膜電位過極化。除此之外,物質P還會調節對河豚毒素不敏感鈉離子通道的表現,以避免中型痛覺神經元的活性因酸的刺激而過度活化。我們的研究結果除了釐清物質P在肌肉中所扮演的角色,還對研發對抗慢性肌肉疼痛的止痛藥物上有很大的幫助。



Substance P (SP) is a neuropeptide well-known for its contribution in the formation of pain sensation. The release of SP in peripheral terminals of nociceptors elicits neurogenic inflammation, which causes vessel dilatation and extravasation followed by peripheral sensitization. However, the release of SP in muscle afferent terminals elicits neither neurogenic inflammation nor sensitization of nociceptors which left its role in muscle afferent neurons undefined. Whole-cell patch clamp recording and retrograde labeling was utilized to characterize the role of SP in gastrocnemius muscle (GM) afferent DRG neurons. Tissue acidosis often leads to the formation of muscle pain; thus the relationship between SP and acid-induced activity was first determined. The acid-induced inward current mediated by ASIC3, the most sensitive proton sensing ion channel was attenuated in the presence SP. It was well established that SP can evoke inward Na+ currents on neurons of different regions and depolarize the membrane potential thus increase neuronal excitability; however, a unique SP-induced outward current (ISP-O) was identified when SP was treated on these neurons. These outward current is believed to act as opposing force against the depolarizing input induced by acid. The ISP-O was especially dominant in the GM populations (50.5%) while the commonly found SP-induced inward current (ISP-I) was found to a lesser extent. The ISP-O was mediated mainly by NK1 receptor and Src family tyrosine kinase dependent but did not require the participation of G-proteins. More importantly, M channels, a ion channel crucial of maintenance of membrane potential were identified to be the ion channel in which the ISP-O was generated. Finally, SP was found to decrease neuronal excitability by attenuating the activity of TTX-sensitive sodium channel and increase action potential firing threshold on medium size GM DRG neurons. Taken together, our findings provide evidence to demonstrate the untypical role of SP in muscle and its implication in designing treatments for acid-induced muscle pain.


Acknowledgments.........................................................................................................I
Chinese Abstract..........................................................................................................II
English Abstract.........................................................................................................III
Table of Contents……………………………………………………………………IV
List of Figures…………………………………………………...……………..….VIII
Abbreviations…………………………………………………………………….......X

Chapter 1. General Introduction
1.1 Preface……………………………………………………………………... 1
1.2 Substance P (SP)…………………………………………………………... 1
1.2.1 Properties of Substance P……………………………………………. 1
1.2.2 Receptors of Substance P……………………………………………. 3
1.2.3 Substance P-induced ionic currents…………………………………. 5
1.2.4 Substance P in treatment of pain…………………………………….. 6
1.2.5 Role Substance P in muscle pain…………………………………….. 7
1.3 Acid sensing ion channel 3 (ASIC3)………………………………………. 7
1.3.1 Acid-sensing ion channels…………………………………………… 8
1.3.2 Properties of ASIC3…………………………………………………. 8
1.3.3 ASIC3, SP and muscle pain………………………………………….. 9
1.4 KCNQ M channel and M current………………………………………….. 9
1.4.1 Properties of M channel……………………………………………... 10
1.4.2 Regulation of M channel activity……………………………………. 10
1.4.3 KCNQ M channel and SP…………………………………………… 11
1.5 The central hypothesis and the purpose of the thesis……………………… 12

Chapter 2. Substance P mediated ionic current on gastrocnemiu muscle afferent DRG neurons
2.1 Introduction………………………………………………………………... 13
2.2 Material and method………………………………………………………. 13
2.2.1 Experimental animal………………………………………………… 13
2.2.2 DRG Primary Culture……………………………………………….. 14
2.2.3 Whole-cell Patch Clamp Recording…………………………………. 14
2.2.4 SP-induced currents on gastrocnemius muscle (GM) afferent DRG neurons……………………………………………………………….. 15
2.2.5 Role of NK receptors in formation ISP-O…………………………….. 15
2.2.6 The difference made between different NK1 receptor agonists……... 16
2.2.7 The dependence of ISP-O on G-protein..……………………………… 16
2.2.8 Validate the independency of G-protein..……………………………. 16
2.2.9 The requirement of ISP-O on phosphotyrosine kinase………………… 17
2.2.10 Validate the need for PTK in ISP-O………………………………….. 17
2.2.11 Investigate the type of PTK involved in the generation of ISP-O…… 17
2.2.12 Identify the type of ion channel that generates ISP-O……………….. 18
2.3.13 Matching the ISP-O with the correct potassium channel…………….. 18
2.3.14 Effect of SP on voltage-induced M current………………………… 18
2.2.15 Data analysis……………………………………………………….. 19
2.3 Result………………………………………………………………………. 19
2.3.1 Fluoro-gold labeled gastrocnemius muscle afferent DRG neurons…. 19
2.3.2 SP-induced currents on gastrocnemius muscle (GM) afferent DRG neurons……………………………………………………………….. 19
2.3.3 The cell size distribution for neurons recorded……………………… 20
2.3.4 The dosage response of ISP-O………………………………………… 20
2.3.5 Role of NK receptors in formation ISP-O.............................................. 21
2.3.6 The difference made between different NK1 receptor agonists…….. 21
2.3.7 The underlying mechanism of ISP-O…………………………………. 22
2.3.7.1 The dependence of ISP-O on G-protein.……………………….. 22
2.3.7.2 Validate the independency of G-protein.……………………... 22
2.3.7.3 The requirement of ISP-O on phosphotyrosine kinase…………. 23
2.3.7.4 Validate the need for PTK in ISP-O……………………………. 23
2.3.7.5 Investigate the type of PTK involved in the generation of ISP-O 24
2.3.7.6 Identify the type of ion channel that generates ISP-O.................. 24
2.3.7.7 Matching the ISP-O with the correct potassium channel………. 25
2.3.7.8 Effect of SP on voltage-induced M current…………………... 26
2.4 Conclusion…………………………………………………………………. 26


Chapter 3. The effect of SP on ASIC3 mediated current on gastrocnemiu muscle afferent DRG neurons
3.1 Introduction………………………………………………………………… 27
3.2 Material and method……………………………………………………….. 27
3.2.1 Experimental animal…………………………………………………. 27
3.2.2 DRG Primary Culture………………………………………………... 27
3.2.3 Whole-cell Patch Clamp Recording…………………………………. 27
3.3.4 Effect of SP on acid-induced ionic current…………………………... 28
3.2.5 Effect of SP on ASIC3-mediated response…………………………... 28
3.2.6 Role of G-protein independent and NK1-R dependent modulation on ASIC3-mediated currents……………………………………………... 29
3.2.7 Participation of PTK in SP mediated modulation on ASIC3 activity... 29
3.2.8 Participation of M current in SP-mediated modulation on ASIC3
activity……………………………………………………………..….. 30
3.2.9 Validate the relationship between SP-induced modulation and ASIC3 mediated current………………………………………………. 30
3.2.10 Relationship between ISP-O and SAS GM DRG neurons…………… 30
3.2.11 Change in SP-induced modulation after pre-injection of acid……… 30
3.2.12 Alternation in NK1 receptor sensitivity to SP on acid pre-injected mice…………………………………………………………………… 30
3.2.13 High dosage of SP restored its modulation on acid pre-injected mice…………………………………………………………………… 31
3.2.14 Data analysis………………………………………………………... 31
3.3 Result………………………………………………………………………. 31
3.3.1 Effect of SP on acid-induced ionic current…………………………... 31
3.3.2 Effect of SP on ASIC3-mediated response…………………………... 31
3.3.3 Role of G-protein independent modulation on ASIC3-mediated currents………………………………………………………………... 33
3.3.4 Involvement of NK1-R dependent modulation on ASIC3-mediated currents………………………………………………………………... 33
3.3.5 Participation of PTK in SP mediated modulation on ASIC3 activity... 33
3.3.6 Participation of M current in SP-mediated modulation on ASIC3 activity………………………………………………………………… 34
3.3.7 Validate the relationship between SP-induced modulation and ASIC3 mediated current………………………………………………………. 35
3.3.8 Relationship between ISP-O and SAS GM DRG neurons…………….. 35
3.3.9 Change in SP-induced modulation after pre-injection of acid……….. 35
3.3.10 The property of ASIC3 remained the same after pre-injection of acid……………………………………………………………………. 36
3.3.11 Alternation in NK1 receptor sensitivity to SP on acid pre-injected mice…………………………………………………………………… 36
3.3.12 High dosage of SP restored its modulation on acid pre-injected mice…………………………………………………………………… 37
3.4 Conclusion…………………………………………………………………. 37





Chapter 4. The modulation of SP on neuronal excitability of gastrocnemius muscle afferent DRG neurons
4.1 Introduction………………………………………………………………... 39
4.2 Material and method………………………………………………………. 39
4.2.1 Experimental animal………………………………………………… 39
4.2.2 DRG Primary Culture……………………………………………….. 39
4.2.3 Whole-cell Patch Clamp Recording…………………………………. 40
4.2.4 Current clamp parameters…………………………………………… 40
4.2.5 Action potential parameters…………………………………………. 40
4.2.6 Action potential threshold…………………………………………… 41
4.2.7 Voltage-Gated Sodium Currents……………………………………... 41
4.2.8 Behavioral Test………………………………………………………. 42
4.2.9 Data Analysis………………………………………………………... 42
4.3 Result………………………………………………………………………. 43
4.3.1 Role of SP in modulating neuronal membrane potential under influence of proton…………………………………………………… 43
4.3.2 Cell size distribution………………………………………………… 44
4.3.3 Analysis of action potential………………………………………….. 44
4.3.4 Role of SP in modulating neuronal membrane potential……………. 44
4.3.5 Effect of SP on action potential firing threshold…………………….. 45
4.3.6 Effect of SP on voltage-gated sodium channel……………………… 45
4.3.7 Effect TTX on ISP-O………………………………………………….. 47
4.3.8 Participation of SP-induced M current on modulation of TTXr INav... 48
4.3.9 SP-mediated change in action potential firing threshold……………. 48
4.3.10 Behavioral validation of NK1 receptor mediated M channel activity………………………………………………………………... 49
4.3.11: The anti-nociceptive role of SP on acid-induced chronic muscle pain…………………………………………………………………… 50
4.4 Conclusion………………………………………………………………… 50

Chapter 5. Discussion.......................................................................................... 51

References............................................................................................................. 60





List of figures and tables
Figure 2.1 GM and Non-GM DRG neurons………………………………... 70
Figure 2.2 SP-mediated currents in muscle afferent DRG neurons………… 71
Figure 2.3 The desensitization for SP-mediated current………………......... 72
Figure 2.4 Cell size distribution for SP-sensitive GM and non-GM DRG neurons…………………………………………………………... 73
Figure 2.5 Dosage response of Isp-o induced by SP…………………………. 74
Figure 2.6 Contribution of different NK receptors to ISP-O…………………. 75
Figure 2.7 Differences in ISP-O generated by SP and SM-SP……………….. 76
Figure 2.8 Role of G-proteins in generation of ISP-O………………………... 77
Figure 2.9 Dependence of G-proteins for GABA-B current………………... 78
Figure 2.10 Phosphotyrosine kianse is required for generation of ISP-O……... 79
Figure 2.11 PTK is required in formation of ISP-O…………………………… 80
Figure 2.12 Augment of ISP-O by phosphatase inhibitor……………………… 81
Figure 2.13 Antagonizing the inhibitory effect of genistein by vanadate……. 82
Figure 2.14 SFK is the PTK that involved in generation of ISP-O……………. 83
Figure 2.15 TEA-Cl indicated ISP-O was generated by a K channel………..… 84
Figure 2.16 Ionic replacement confirmed the participation of K channel…… 85
Figure 2.17 ISP-O is generated by the opening of KCNQ M channel………… 86
Figure 2.18 Generation of ISP-O by KCNQ M channel is confirmed…………. 87
Figure 2.19 SP induced further opening of M channel on GM DRG neurons.. 88
Figure 2.20 Quantification of SP-induced change in M current……………... 89

Figure 3.1 SP had diverse effect on acid-induced currents…………………. 90
Figure 3.2 Modulation of SP in cell-types specific fashion………………… 93
Figure 3.3 Effect of SP on ASIC3-mediated currents………………………. 94
Figure 3.4 Effect of SP was translated by NK1 receptor…………………… 95
Figure 3.5 The role of phosphotyrosine kinase on SP-mediated modulation. 96
Figure 3.6 SP-mediated modulation was inhibited by M channel blocker…. 97
Figure 3.7 SP-mediated modulation on ASIC3 KO mice…………………... 98
Figure 3.8 The ISP-O and ASIC3 mediated currents…………………………. 99
Figure 3.9 Effect of SP on mice pre-injected with acid…………………….. 100
Figure 3.10 Change of acid-induced current after pre-injected with acid…… 101
Figure 3.11 Decrease of ISP-O amplitude after pre-injection of acid……….… 102
Figure 3.12 High dosage of SP restores its effect on ASIC-3 mediated current…………………………………………………………… 103


Figure 4.1 SP antagonized the effect of acid on GM DRG neurons……...… 104
Figure 4.2 Cell size distribution for neurons studied in current clamp…...… 105
Figure 4.3 SP-induced hyperpolarization…………………………………… 107
Figure 4.4 SP increased the action potential firing threshold……….……… 108
Figure 4.5 Effects of M Channel Blocker on INav of medium size GM neurons…………………………………………………………... 109
Figure 4.6 Effects of M Channel Blocker on INav of small size GM neurons. 110
Figure 4.7 TTX generated no effect on ISP-O………………………………... 111
Figure 4.8 SP decreased TTXr INav…………………………………………. 112
Figure 4.9 The AP threshold of GM neurons from pre-treated mice……..… 113
Figure 4.10 SP can modulate the activity of TTXr Nav and hence neuronal excitability………………………………………………………. 114
Figure 4.11 Modulation of SP-induced M current in Acid-induced Muscle Pain Model………………………………………………………. 115
Figure 4.12 Schematic Model for SP Mediated Inhibition on ASIC3 Signaling………………………………………………………… 116

Table 3-1 Summary of SP effect on acid-evoked currents…………………. 92
Table 4-1 The action potential parameter parameters……………………… 106

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