臺灣博碩士論文加值系統

杏仁體中核(central amygdala nucleus, CeA)的電性或化學性刺激會抑制脊髓的痛覺傳遞，進而產生止痛作用。當CeA投射興奮性訊息至同側的中腦導水管周圍灰質(periaqueductal gray, PAG)時，可以活化PAG到頭腹中側延腦(rostral ventromedial medulla, RVM)的下傳止痛神經迴路(descending antinociceptive neuronal circuitry)。近年來，許多證據指出發炎性慢性疼痛(chronic inflammatory pain)是由於大腦神經可塑性改變而成，進而影響下傳調節途徑去控制脊髓背角(spinal dorsal horn)的痛覺傳遞。此外，許多研究也顯示當組織發炎或周圍神經產生病變，神經膠細胞(glial cells)會活化，而其後釋放的膠細胞傳導物質(gliotransmitters)或發炎細胞素(proinflammatory cytokines)則會藉由調節神經活性及突觸強度進一步促成痛覺過敏(hyperalgesia)。根據這些研究結果可以推測發炎性慢性疼痛引起的痛覺過敏可能是因為活化CeA區域神經膠細胞造成CeA-PAG投射神經元的突觸可塑性產生改變，進一步削弱了CeA-PAG-RVM下傳止痛神經迴路的活性。為了證明這個假設，將發炎物質Complete Freund's adjuvant(CFA)皮下注射到三到四週大的大鼠後腳掌，引發其腳掌發紅水腫。在24小時後，與皮下注射Saline的控制組相比，發現CFA會造成大鼠腳掌產生機械性痛覺異常(mechanical allodynia)，且此症狀持續至少7天。其後，將黃綠螢光微粒(yellow-green fluorescent microspheres)微管注射到大鼠PAG腹側位置，四天後便可以在牠們的CeA中間區域(CeAM)發現CeA-PAG投射神經元具有螢光標示。接著，利用腦切片進行全細胞膜電位箝制記錄，此實驗顯示在注射CFA的老鼠其CeA-PAG投射神經元的自發性微興奮性突觸後電流(spontaneous miniature EPSCs, mEPSCs)之頻率有降低的現象，但並不影響mEPSCs的振幅大小。而注射CFA亦可增加自發性微抑制性突觸後電流(spontaneous miniature IPSCs, mIPSC)的頻率，且也不改變mIPSCs的振幅平均值。除此之外，注射CFA會增加CeAM腦區的星形膠細胞(astrocytes)，並使其產生肥大(hypertrophy)的現象。然而，在大鼠CeAM腦區微管注射星形膠細胞抑制劑fluorocitrate，則可以明顯降低星形膠細胞的活化及減緩CFA引發的機械性痛覺異常。Fluorocitrate亦可以削弱CFA所降低的興奮性麩氨酸突觸傳遞，以及減弱CFA所促進的抑制性γ-氨基丁酸(GABA)突觸傳遞。總結，我們的研究強烈顯示星形膠細胞的活化參與了周邊發炎誘發的CeAM-PAG投射神經元突觸可塑性，進而削弱CeAM-PAG下傳止痛神經迴路，並造成機械性痛覺異常。

Electrical or chemical stimulation of central amygdala nucleus (CeA) inhibits spinal pain transmission and produces an analgesic effect. CeA sends a dense ipsilateral excitatory projection to midbrain periaqueductal gray (PAG) and activates PAG-rostral ventromedial medulla (RVM) descending anti-nociceptive neuronal circuitry. Recently, several lines of evidence suggest that chronic inflammatory pain is due to long-term neuroplastic changes in brain regions, which control pain transmission in the spinal dorsal horn through descending modulatory pathways. Recent studies also suggest that activation of glial cells and a subsequent release of gliotransmitters or proinflammatory cytokines, which modulate neuronal activity and synaptic strength, contribute to the development of pain hypersensitivity after nerve injury or peripheral inflammation. Thus, it is very likely that during chronic inflammatory pain, activation of glial cells in CeA could induce hyperalgesia by causing synaptic plasticity of CeA-PAG projection neurons and attenuate the activity of CeA-PAG-RVM descending antinociceptive circuitry. Intraplantar injection of Complete Freund's adjuvant (CFA) resulted in erythema and edema at the site of injection. Mechanical allodynia was observed in CFA-injected rats within 24 hours after CFA injection and lasted about 7 days. Four days after microinjecting yellow-green fluorescent microspheres into the lateral and ventrolateral PAG of 3 to 4 weeks-old saline or CFA-injected rats, fluorescently labeled CeA-PAG projection neurons were mainly found in the medial division of central amygdala nucleus (CeAM). CFA administration decreased the frequency of spontaneous miniature EPSCs (mEPSCs) in CeAM-PAG projection neuron from CFA-treated rats in the absence of change in the mean amplitude of mEPSCs. CFA injection also increased the frequency of spontaneous IPSCs in CeAM-PAG projection neurons without significantly affecting the mean amplitude of mIPSCs. CFA injection induced the hypertropy and an increase in the number of GFAP-positive astrocytes in the CeAM region. Furthermore, microinjection of fluorocitrate, a metabolic inhibitor of astrocytes, into CeAM area significantly attenuated astrocyte activation and CFA-induced mechanical allodynia. Fluorocitrate also attenuated CFA-induced impairment of excitatory glutamatergic transmission and CFA-induced enhancement of inhibitory GABAergic transmission in CeAM-PAG projection neurons. Our results strongly suggest that astroglial activation is involved in peripheral inflammation-induced synaptic plasticity of CeAM-PAG projection neurons, which impairs the activity of CeAM-PAG descending antinociceptive pathway and causes resulting mechanical allodynia.

指導教授推薦書
口試委員會審定書
授權書 iii
致謝 iv
Abstract (Chinese) vi
Abstract (English) viii
Abbreviations x
Contents xii
Figure contents xv
I. Introduction 01
1.1 Chronic pain 01
1.2 Peripheral nerve injury or inflammation-induced change in descending pain modulation pathways 03
1.3 CeA-PAG-RVM descending antinociceptive circuitry 04
1.4 Peripheral inflammation and CeA-PAG pain modulatory pathway 06
1.5 Glia-neuron interaction in CeA during peripheral inflammation-induced chronic pain 07
II. Specific Aim and Significance 12
III. Experimental Procedures 14
3.1 Retrograde labeling of rat CeA-PAG projection neurons 14
3.2 Induction of chronic inflammation 14
3.3 Behavioral tests for mechanical allodynia 15
3.4 Brain slice preparation 15
3.5 Whole-cell patch-clamp recordings 16
3.6 Microinjection of fluorocitrate 17
3.7 Immunohistochemistry 17
3.8 Statistics 18
IV. Results 19
4.1 Intraplantar administration of CFA induces mechanical allodynia 19
4.2 Retrograde labeling of CeAM-PAG projection neurons 19
4.3 Intraplantar injection of CFA attenuates excitatory glutamatergic transmission in CeAM-PAG projection neurons 21
4.4 Intraplantar injection of CFA strengthens inhibitory GABAergic transmission in CeAM-PAG projection neurons 22
4.5 Intraplantar administration of CFA induces astroglial activation in the CeAM 23
4.6 Astroglial activation inhibitor fluorocitrate inhibits CFA-induced mechanical allodynia 24
4.7 Fluorocitrate attenuates CFA-induced impairment of excitatory glutamatergic transmission and CFA-induced enhancement of inhibitory GABAergic transmission in CeAM-PAG projection neurons 24
V. Discussion 26
VI. References 32
VII. Figures 48
VIII. Table 72

FIGURE CONTENTS
Figure 1. Endogenous CeA-PAG-RVM descending antinociceptive circuitry that modulates pain transmission in the spinal dorsal horn 48
Figure 2. Intraplantar administration of CFA induces mechanical allodynia by von Frey filaments. 50
Figure 3. Retrograde labeling of CeAM-PAG projection neurons 52
Figure 4. Whole-cell patch-clamp recordings of visualized CeAM-PAG projection neurons in brain slices 54
Figure 5. Intraplantar injection of CFA inhibits spontaneous excitatory glutamatergic transmission in CeAM-PAG projection neurons 56
Figure 6. CFA inhibits glutamatergic transmission in CeAM-PAG projection neurons through a presynaptic mechanism 58
Figure 7. Intraplantar injection of CFA strengthens spontaneous inhibitory GABAergic transmission in CeAM-PAG projection neurons 60
Figure 8. CFA augments spontaneous GABAergic transmission in CeAM-PAG projection neurons via a presynaptic mechanism 62
Figure 9. Intraplantar injection of CFA induces astroglial activation in the CeAM 64
Figure 10. Microinjection of fluorocitrate, a metabolic inhibitor of astrocytes, into the CeAM significantly attenuates CFA-induced hyperalgesia 66
Figure 11. Fluorocitrate blocks CFA-induced attenuation of spontaneous glutamatergic transmission in CeAM-PAG projection neurons 68
Figure 12. Fluorocitrate attenuates CFA-induced enhancement of spontaneous GABAergic transmission in CeAM-PAG projection neurons 70

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