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https://nccur.lib.nccu.edu.tw/handle/140.119/157157
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| Title: | 探討甲基甘氨酸衍生物對神經性疼痛的鎮痛機轉
Exploring the Mechanisms Underlying Analgesic Effects of N-Methyl-Glycine Derivatives on Neuropathic Pain |
| Authors: | 詹銘煥 |
| Contributors: | 神科所 |
| Keywords: | 鎮痛;神經性疼痛;NMDA受體;甲基甘氨酸衍生物;內側前額葉皮質;脊髓
Analgesia;Neuropathic pain;NMDA receptor;N-methyl glycine derivatives;Medial prefrontal cortex;Spinal cord |
| Date: | 2022-02 |
| Issue Date: | 2025-05-29 11:56:46 (UTC+8) |
| Abstract: | 神經性疼痛是重要的公共健康問題，降低患者的生活品質。目前用於治療神經性疼痛藥物的療效有限且副作用嚴重，對疼痛患者未能發揮適當療效，本研究旨在開發有效且安全的新型治療藥物。目前疼痛治療藥物大多聚焦於腦和脊髓，先前研究指出活化大腦內側前額葉皮質和杏仁核中N-甲基-D-天冬氨酸(NMDA)受體甘氨酸結合位點導致加強下行疼痛調節迴路，達成緩解神經性疼痛行為。然而激活脊髓甘氨酸/NMDA受體卻導致疼痛。因此，透過特定的甘氨酸/NMDA受體調節劑可能是治療神經性疼痛的新策略。我們目前研究發現二甲基甘氨酸和三甲基甘氨酸為甘氨酸/NMDA受體部分致效劑。假設在神經性疼痛的條件下，二甲基甘氨酸和三甲基甘氨酸可以增強腦中尤其是內側前額葉皮質NMDA受體的活性，但會減弱脊髓NMDA受體活性，達到拮抗神經性疼痛的作用。由於肌氨酸曾被發現具有對抗神經性疼痛作用，因此本研究計畫將利用順鉑誘導神經性疼痛和慢性缺血後疼痛之小鼠模型比較此三種甲基甘氨酸衍生物，包含肌氨酸、二甲基甘氨酸和三甲基甘氨酸，對神經性疼痛的潛在療效。將進行四個研究目標檢驗假說並探索其藥理機轉。目標1：評估甲基甘氨酸衍生物在神經性疼痛小鼠模型中的鎮痛作用。目標2：檢測甲基甘氨酸衍生物拮抗神經性疼痛的作用腦區。 目標3：檢測甲基甘氨酸衍生物藉由調控NMDA受體介導的神經性傳遞對抗神經性疼痛。目標4: 檢測單胺神經系統是否參與甲基甘氨酸衍生物的鎮痛活性。根據四個目標，將執行以下實驗設計。第一個目標將透過全身性施予甲基甘氨酸衍生物至順鉑誘導神經性疼痛和慢性缺血後疼痛之小鼠評估拮抗神經性疼痛的作用，分析並比較甲基甘氨酸衍生物對神經性疼痛的各自功效。目標2將探討甲基甘氨酸衍生物的鎮痛和抗痛覺過敏作用的標的區域，進行鞘內、腦室內和內側前額葉皮質內注射甲基甘氨酸衍生物以發掘其鎮痛效用在中樞系統的作用位點。目標3將進一步確認甘氨酸/NMDA受體介導的突觸傳遞參與甲基甘氨酸衍生物的鎮痛作用。目標4將檢驗正腎上腺素和血清素的單胺傳遞系統關聯甲基甘氨酸衍生物拮抗神經性疼痛之效用。本研究將闡明甲基甘氨酸衍生物對神經性疼痛的鎮痛效用和藥理機轉，藉由了解甲基甘氨酸衍生物特定與神經性疼痛相關的標的受體和作用區域，開啟治療神經性疼痛新藥開發的新領域。
Neuropathic pain (NeuP) is an essential public health problem and depreciates patients’ life quality. Since the recent drugs used for pain treatment have limited efficacy and severe adverse effects, patients with NeuP are not treated optimally. This study will expect to develop novel medications to relieve pain with efficacious and safe property. Currently, the medication for NeuP treatment is focusing on the brain and spinal cord. Previous research indicated that activation of N-methyl-D-aspartate receptors (NMDARs) at glycine binding site in medial prefrontal cortex (mPFC) and amygdala leads to enhancing the descending pain modulating circuit and relieving NeuP behavior. Instead, activation of spinal NMDAR contributes to development of NeuP. Thus, targeting to glycine binding site on NMDAR complex by specific NMDAR modulators might be a novel strategy for treatment of NeuP. We have found that N,N-dimethylglycine (DMG) and N,N,N-trimethylglycine (TMG) are the partial agonists of NMDAR glycine binding site. In NeuP condition, it is hypothesized that DMG and TMG can enhance NMDAR activity in the brain, especially mPFC, but attenuate the spinal NMDAR activity, leading to anti-NeuP. As N-methylglycine (sarcosine) exhibits anti-neuropathic effect, this project will use cisplatin-induced neuropathic pain and chronic post-ischemia pain mouse models to compare the potential efficacies of three N-methylglycine derivatives (MGDs), including sarcosine, DMG, and TMG, against NeuP. Four specific aims will be conducted to test the hypothesis and explore the underlying mechanisms. Aim 1: To evaluate the analgesic activity of MGDs in neuropathic pain mouse models.Aim 2. To determine the target regions for MGDs against neuropathic pain Aim 3: To determine the MGDs-induced anti-neuropathic pain via modulating NMDAR-mediated neuropathic transmission.Aim 4: To determine whether monoaminergic systems are involved in the analgesic activity of MGDs in neuropathic mice.According to the four specific aims, the following experimental designs will be performed. The first aim will evaluate the anti-neuropathic actions of MGDs by systemic administration in both cisplatin-induced neuropathic pain and chronic post-ischemia pain mouse models. The respective efficacy of MGDs on NeuP will be analyzed and compared. Aim 2 will explore the target region of the anti-allodynia and anti-hyperalgesia actions of MGDs. The intrathecal, intracerebroventricular and intra-mPFC injection of MGDs will be conducted to inform the acting locations of MGDs to exert their analgesic responses within CNS. Aim 3 will further identify central glycine/NMDAR-mediated synaptic transmission involved in analgesic effect of MGDs. Aim 4 will determine whether the anti-allodynia and anti-hyperalgesia activity of MGDs associated with noradrenergic and serotonergic neurotransmission in neuropathic mice. Our study will reveal the analgesic profiles of MGDs on NeuP and elucidate their underlying mechanisms. Understanding the specific target receptors and target regions of MDGs for NeuP might open up a promising new territory for the development of novel drugs to meet the needs for treatment of NeuP. |
| Relation: | 科技部, MOST109-2314-B004-001, 109.08-110.07 |
| Data Type: | report |
| Appears in Collections: | [神經科學研究所] 國科會研究計畫
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