Suppression of stretch reflex activity after spinal or systemic treatment with AMPA receptor antagonist NGX424 in rats with developed baclofen tolerance
Suppression of stretch reflex activity after spinal or systemic treatment with AMPA receptor antagonist NGX424 in rats with developed baclofen tolerance
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DOI：
10.1111/j.1476-5381.2010.00954.x
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发表时间：
2010-11-01
影响因子：
7.3
通讯作者：
Marsala, Martin
中科院分区：
文献类型：
--
作者：
Oshiro, Masakatsu;Hefferan, Michael P.;Marsala, Martin
背景和目的巴氯芬（一种 GABA(B) 受体激动剂）是临床实践中最常用的抗痉挛剂。虽然脊髓或全身给药时有效，但逐渐耐受的发展严重限制了其长期使用。本研究的目的是表征选择性 AMPA 受体拮抗剂 NGX424 鞘内或全身治疗后对巴氯芬耐受性大鼠牵张反射活动 (SRA) 和背景肌肉活动 (BMA) 的治疗效力。 实验方法将动物暴露于脊髓缺血 10 分钟，以诱导 BMA 和 SRA 增加。选定的动物被植入鞘内PE-5导管并鞘内输注巴氯芬（1μg中心点h-1）14天。在巴氯芬输注之前和之后，每隔 2 天测量一次 BMA 和 SRA 的变化。产生巴氯芬耐受性后，向动物鞘内（1μg）或皮下（3、6或12mg中心点kg-1）注射NGX424，并测量BMA和SRA的变化。 主要结果NGX424的鞘内或全身给药显着抑制巴氯芬耐受动物的BMA和SRA。这种作用是剂量依赖性的。注射 1 μg（鞘内）或 12 mg 中心点 kg-1（皮下注射）NGX424 后观察到的 BMA 和 SRA 抑制程度与巴氯芬输注前 5 天期间观察到的相似。结论和意义这些数据表明，使用 NGX424 可以作为一种有效疗法来调节巴氯芬难治性或耐受性患者的慢性痉挛状态链接文章本文由 Gomez-Soriano 等人评论，本期第 972-975 页。要查看此评论，请访问 http://dx.doi.org/10.1111/j.1476-5381.2010.00964.x。
BACKGROUND AND PURPOSEBaclofen (a GABA(B) receptor agonist) is the most commonly used anti-spasticity agent in clinical practice. While effective when administered spinally or systemically, the development of progressive tolerance represents a serious limitation for its long-term use. The goal of the present study was to characterize the treatment potency after intrathecal or systemic treatment with the selective AMPA receptor antagonist NGX424 on stretch reflex activity (SRA) and background muscle activity (BMA) in rats with developed baclofen tolerance.EXPERIMENTAL APPROACHAnimals were exposed to 10 min of spinal ischaemia to induce an increase in BMA and SRA. Selected animals were implanted with an intrathecal PE-5 catheter and infused intrathecally with baclofen (1 mu g center dot h-1) for 14 days. Before and after baclofen infusion, changes in BMA and SRA were measured at 2 day intervals. After development of baclofen tolerance, the animals were injected intrathecally (1 mu g) or subcutaneously (3, 6 or 12 mg center dot kg-1) with NGX424, and changes in BMA and SRA were measured.KEY RESULTSIntrathecal or systemic delivery of NGX424 significantly suppressed the BMA and SRA in baclofen-tolerant animals. This effect was dose dependent. The magnitude of BMA and SRA suppression seen after 1 mu g (intrathecal) or 12 mg center dot kg-1 (s.c.) of NGX424 injection was similar to that seen during the first 5 days of baclofen infusion.CONCLUSIONS AND IMPLICATIONSThese data demonstrate that the use of NGX424 can represent an effective therapy to modulate chronic spasticity in patients who are refractory or tolerant to baclofen treatment.LINKED ARTICLEThis article is commented on by Gomez-Soriano et al., pp. 972-975 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2010.00964.x.