Role of Renin-angiotensin axis on its gene expression and anti-sense gene therapy in patients with neuropathic pain

肾素-血管紧张素轴对其基因表达的影响及神经病理性疼痛患者的反义基因治疗

• 批准号: 14571429
• 负责人: KIMURA Tomomasa
• 金额: $ 2.24万
• 依托单位: Nagoya University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14571429/
• 关键词: Neuropathic Pain; Renin-Angiotensin; ACE polymorphism; Angiotensinogen plymorphism; Antisense-ODN; SHR; Paraventricular nucleus; Bennet model

The aim of this study was to explore (1) whether renin-angiotensin axis associates with neuropathic pain and (2) the efficacy of antisense therapy on treatment of neuropathic pain.1) Clinical study :ACE gene polymorphism (DD and II homozygotes, and ID heterozygotes) associates the genetic risk factor for neuropathic pain. The distribution of the DD, ID and II genotypes in the study group is 33%, 33% and 33%, respectively. ACE activity was significantly higher in subjects with the ACE DD genotype than subjects with the ID and II genotypes. No significant difference in heart rate and blood pressure variabilities, plasma renin activity, angiotensin I and II was detected among the ACE genotypes. The frequency of the ACE DD genotype in the present population (33%) was higher than those previously described in other normal populations of the same race (20%)In addition, the frequency of the ACE DD genotype in CRPS type I was higher than those in CRPF type II.It is possible that the DD genotyp … More e favors the development of neuropathic pain as well as cardiovascular disease, perhaps through the presence of higher ACE concentrations. Elevated ACE activity in these subjects may result in increased angiotensin II levels in the effector site, and this might be a mechanism underlying the association between the ACE deletion polymorphism and the increased genetic risk for susceptibility to neuropathic pain.2) Basic study :We investigated the effects of intrathecal infusion of naloxone on mechanical hypersensitivity and the relationship between high blood pressure and the analgesia in SHR. Measurements were performed before and 15min after the intrathecal administration of naloxone. There was no significant differences in systolic blood pressure after the intrathecal infusion of naloxone. This finding might indicate that naloxone had blocked both μ-receptor which had a hypertensive action and κ-receptor which had a hypotensive action.Anti-sense gene therapy for angiotensin II type 1 in SHR showed decreased blood pressure by 30mmHg and unchanged mechanical allodynia, suggesting that central rennin-angiotensin axis showed to decrease nociception, while peripheral rennin-angiotensin axis increased nocecption.In conclusion, renin-angiotensin system may play dual effects on mononeuropathic pain : relieved heat allodynia due to central opioid system, and aggravation of peripheral mononeuropathy arising from renin-angiotensin induced vasospastic phenomenon. Further investigation may be needed concerning the genetic predisposition for mononeuropathic pain in relation to hypertension. Less

本研究的目的是探讨（1）肾素-血管紧张素轴是否与神经病理性疼痛有关，（2）反义治疗对神经病理性疼痛的疗效。1）临床研究：ACE基因多态性（DD和II纯合子，ID杂合子）与神经病理性疼痛的遗传危险因素有关。研究组DD、ID和II基因型分布分别为33%、33%和33%。ACE DD基因型患者的ACE活性显著高于ID和II基因型患者。ACE基因型间心率、血压变异性、血浆肾素活性、血管紧张素I和血管紧张素II无显著性差异。ACE DD基因型在本人群中的分布频率（33%）高于同种族其他正常人群（20%）。此外，ACE DD基因型在CRPS Ⅰ型中的分布频率高于CRPF Ⅱ型，提示ACE DD基因型可能是CRPS Ⅰ型的一个重要遗传因素。 ...更多信息 E可能通过较高的ACE浓度促进神经性疼痛和心血管疾病的发展。这些受试者中升高的ACE活性可能导致效应部位血管紧张素II水平升高，这可能是ACE缺失多态性与神经病理性疼痛易感性遗传风险增加之间相关性的机制。2）基础研究：我们研究了鞘内注射纳洛酮对SHR机械性超敏反应的影响以及高血压与镇痛之间的关系。在鞘内注射纳洛酮之前和之后15分钟进行测量。鞘内注射纳洛酮后，收缩压无显著差异。这一结果可能表明纳洛酮同时阻断了具有高血压作用的μ-受体和具有降压作用的κ-受体。反义基因治疗SHR的血管紧张素II 1型可使血压下降30 mmHg，而机械性异常性疼痛无变化，表明中枢肾素-血管紧张素轴减少了伤害性感受，而外周肾素-血管紧张素轴增加了伤害性感受。肾素-血管紧张素系统在单神经痛中可能具有双重作用：减轻中枢阿片系统引起的热异常性疼痛，以及加重由肾素-血管紧张素诱导的血管痉挛现象引起的外周单神经病。可能需要进一步的调查有关的遗传易感性单神经性疼痛与高血压。少

项目成果

鳥居 圭: "Paraplegic Painの治療経験"日本ペインクリニック学会誌. 10. 72-72 (2002)

Kei Torii：“治疗截瘫疼痛的经验”日本疼痛诊所杂志 10. 72-72 (2002)。

木村 智政: "硬膜外電気刺激療法時の脳機能画像変化"日本ペインクリニック学会誌. 10. 352-352 (2003)

Tomomasa Kimura：“硬膜外电刺激治疗期间脑功能成像的变化”日本疼痛诊所杂志 10. 352-352 (2003)。

鳥居 圭: "ケタミン点滴療法が有効であった視床痛の1例(SPECT, PET画像を含めて)"日本ぺインクリニック学会誌. 10. 417-417 (2003)

Kei Torii：“氯胺酮滴注疗法有效的丘脑疼痛病例（包括 SPECT 和 PET 图像）” 日本疼痛临床医师学会杂志 10. 417-417 (2003)。

鳥居 圭: "ケタミン点滴療法が有効であった視床痛の1例(SPECT、PET画像を含めて)"日本ペインクリニック学会誌. 10. 417-417 (2003)

Kei Torii：“氯胺酮滴注疗法有效的丘脑疼痛病例（包括 SPECT 和 PET 图像）” 日本疼痛临床医师学会杂志 10. 417-417 (2003)。

鳥居 圭: "星状神経節ブロックに伴い重度の高血圧をきたした7症例"Journal of Anesthesia. 17. 303-303 (2003)

Kei Torii：“与星状神经节阻滞相关的严重高血压的七例”麻醉杂志 17. 303-303 (2003)。