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

本研究旨在探讨(1)肾素-血管紧张素轴是否与神经性疼痛相关；(2)反义疗法对神经性疼痛的治疗效果。1)临床研究：ACE基因多态性（DD、II纯合子、ID杂合子）与神经性疼痛的遗传危险因素相关。DD、ID和II基因型在研究组中的分布分别为33%、33%和33%。ACE DD基因型受试者的ACE活性显著高于ID和II基因型受试者。不同ACE基因型患者的心率、血压变异性、血浆肾素活性、血管紧张素I和II无显著差异。目前人群中ACE DD基因型的频率（33%）高于其他同种族正常人群（20%）。此外，CRPS I型患者ACE DD基因型的频率高于CRPF II型患者。可能DD基因型更有利于神经性疼痛和心血管疾病的发展，这可能是通过存在较高的ACE浓度。这些受试者的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缺失多态性与神经性疼痛易感性遗传风险增加之间关联的一种机制。2)基础研究：探讨鞘内灌注纳洛酮对SHR患者机械超敏反应的影响及高血压与镇痛的关系。测量分别在纳洛酮鞘内给药前和给药后15min进行。鞘内输注纳洛酮后收缩压无显著差异。这可能说明纳洛酮同时阻断了具有降压作用的μ受体和具有降压作用的κ受体。反义基因治疗的血管紧张素II型1型SHR患者血压下降30mmHg，机械性异常痛未发生改变，提示中央肾素-血管紧张素轴减少痛觉，而外周肾素-血管紧张素轴增加痛觉。综上所述，肾素-血管紧张素系统对单神经病变疼痛可能具有双重作用：一是中枢阿片系统引起的热异常性疼痛得到缓解，二是肾素-血管紧张素引起的血管痉挛现象加重周围单神经病变。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。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