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

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相关。研究组中DD、ID和II型的分布分别为33%、33%和33%。ACE DD基因携带者的ACE活性显著高于ID和II基因携带者。在心率和血压变异性、血浆肾素活性、血管紧张素I和血管紧张素II方面，不同的ACE基因型之间没有显著差异。本组人群血管紧张素转换酶基因DD型频率(33%)高于其他同种族正常人群(20%)。此外，CRPI型…的DD型频率高于II型。更多的血管紧张素转换酶可能通过较高的血管紧张素转换酶浓度促进神经性疼痛和心血管疾病的发生。在这些受试者中，ACE活性升高可能导致效应部位血管紧张素II水平升高，这可能是ACE缺失多态与神经病理性疼痛易感性增加遗传风险之间关联的机制之一。2)基础研究：我们研究了鞘内注射纳洛酮对自发性高血压大鼠机械过敏的影响以及高血压与镇痛的关系。分别在鞘内注射纳洛酮前和给药后15min进行测量。鞘内注射纳洛酮后，大鼠的收缩压无明显变化。这一发现可能表明纳洛酮阻断了具有降压作用的μ受体和具有降压作用的κ受体。反义基因治疗使自发性高血压大鼠血压降低30 mmHg，机械痛无明显变化，提示中枢性肾素-血管紧张素轴减少伤害性感觉，而外周肾素-血管紧张素轴增加伤害性。综上所述，肾素-血管紧张素系统可能在单神经性疼痛中起双重作用：缓解中枢阿片系统引起的热痛，加重肾素-血管紧张素诱导的血管痉挛现象引起的外周单神经病变。可能需要进一步研究与高血压相关的单神经性疼痛的遗传易感性。较少

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