Nielsen Carsten K, Lewis Richard J, Alewood Dianne, Drinkwater Roger, Palant Elka, Patterson Margaret, Yaksh Tony L, McCumber Damon, Smith Maree T
School of Pharmacy, The University of Queensland, Brisbane, Qld, Australia.
Pain. 2005 Nov;118(1-2):112-24. doi: 10.1016/j.pain.2005.08.002. Epub 2005 Sep 9.
Xen2174 is a structural analogue of Mr1A, a chi-conopeptide recently isolated from the venom of the marine cone snail, Conus marmoreus. Although both chi-conopeptides are highly selective inhibitors of the norepinephrine transporter (NET), Xen2174 has superior chemical stability relative to Mr1A. It is well-known that tricyclic antidepressants (TCAs) are also potent NET inhibitors, but their poor selectivity relative to other monoamine transporters and various G-protein-coupled receptors, results in dose-limiting side-effects in vivo. As TCAs and the alpha(2)-adrenoceptor agonist, clonidine, have established efficacy for the relief of neuropathic pain, this study examined whether intrathecal (i.t.) Xen2174 alleviated mechanical allodynia in rats with either a chronic constriction injury of the sciatic nerve (CCI-rats) or an L5/L6 spinal-nerve injury. The anti-allodynic responses of i.t. Mr1A and i.t. morphine were also investigated in CCI-rats. Paw withdrawal thresholds were assessed using calibrated von Frey filaments. Bolus doses of i.t. Xen2174 produced dose-dependent relief of mechanical allodynia in CCI-rats and in spinal nerve-ligated rats. Dose-dependent anti-allodynic effects were also produced by i.t. bolus doses of Mr1A and morphine in CCI-rats, but a pronounced 'ceiling' effect was observed for i.t. morphine. The side-effect profiles were mild for both chi-conopeptides with an absence of sedation. Confirming the noradrenergic mechanism of action, i.t. co-administration of yohimbine (100 nmol) with Xen2174 (10 nmol) abolished Xen2174s anti-allodynic actions. Xen2174 appears to be a promising candidate for development as a novel therapeutic for i.t. administration to patients with persistent neuropathic pain.
Xen2174是Mr1A的结构类似物，Mr1A是一种最近从海洋芋螺Conus marmoreus的毒液中分离出的芋螺毒素。尽管这两种芋螺毒素都是去甲肾上腺素转运体（NET）的高度选择性抑制剂，但相对于Mr1A，Xen2174具有更好的化学稳定性。众所周知，三环类抗抑郁药（TCA）也是有效的NET抑制剂，但其相对于其他单胺转运体和各种G蛋白偶联受体的选择性较差，导致体内出现剂量限制性副作用。由于TCA和α2肾上腺素能受体激动剂可乐定已被证实对缓解神经性疼痛有效，本研究考察了鞘内注射Xen2174是否能减轻坐骨神经慢性压迫损伤（CCI大鼠）或L5/L6脊神经损伤大鼠的机械性异常性疼痛。还在CCI大鼠中研究了鞘内注射Mr1A和鞘内注射吗啡的抗异常性疼痛反应。使用校准的von Frey细丝评估爪部退缩阈值。鞘内注射大剂量Xen2174可使CCI大鼠和脊神经结扎大鼠的机械性异常性疼痛得到剂量依赖性缓解。鞘内注射大剂量Mr1A和吗啡在CCI大鼠中也产生了剂量依赖性抗异常性疼痛作用，但鞘内注射吗啡观察到明显的“天花板”效应。两种芋螺毒素的副作用都很轻微，没有镇静作用。证实了去甲肾上腺素能作用机制，鞘内注射育亨宾（100 nmol）与Xen2174（10 nmol）共同给药可消除Xen2174的抗异常性疼痛作用。Xen2174似乎是一种很有前景的候选药物，有望开发成为一种新型治疗药物，用于向持续性神经性疼痛患者鞘内给药。
