Masocha Willias, Parvathy Subramanian S
Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Kuwait University , Safat , Kuwait.
PeerJ. 2016 Dec 15;4:e2798. doi: 10.7717/peerj.2798. eCollection 2016.
There is a dearth of drugs to manage a dose-limiting painful peripheral neuropathy induced by paclitaxel in some patients during the treatment of cancer. Gamma-aminobutyric acid transporter-1 (GAT-1) whose expression is increased in the brain and spinal cord during paclitaxel-induced neuropathic pain (PINP) might be a potential therapeutic target for managing PINP. Thus, our aim was to evaluate if systemic administration of a GAT-1 inhibitor ameliorates PINP.
The reaction latency to thermal stimuli (hot plate test; at 55 °C) and cold stimuli (cold plate test; at 4 °C) of female BALB/c mice was recorded before and after intraperitoneal treatment with paclitaxel, its vehicle, and/or a selective GAT-1 inhibitor NO-711. The effects of NO-711 on motor coordination were evaluated using the rotarod test at a constant speed of 4 rpm or accelerating mode from 4 rpm to 40 rpm over 5 min.
The coadministration of paclitaxel with NO-711 3 mg/kg prevented the development of paclitaxel-induced thermal hyperalgesia and cold allodynia at day 7 after drug treatment. NO-711 at 3 mg/kg produced antihyperalgesic activity up to 1 h and antiallodynic activity up to 2 h in mice with established paclitaxel-induced thermal hyperalgesia and cold allodynia. No motor deficits were observed with NO-711 at a dose of 3 mg/kg, whereas a higher dose 5 mg/kg caused motor impairment and reduced mean time spent on the rotarod at a constant speed of 4 rpm. However, at a rotarod accelerating mode from 4 rpm to 40 rpm over 5 min, NO-711 3 mg/kg caused motor impairment up to 1 h, but had recovered by 2 h.
These results show that systemic administration of the GAT-1 inhibitor NO-711 has preventative and therapeutic activity against paclitaxel-induced thermal hyperalgesia and cold allodynia. NO-711's antiallodynic effects, but not antihyperalgesic effects, were independent of its motor impairment/sedation properties. Thus, low doses of GAT-1 inhibitors could be useful for the prevention and treatment of PINP with proper dose titration to reduce motor impairment/sedation side effects.
在癌症治疗过程中，一些患者因紫杉醇诱导的剂量限制性疼痛性周围神经病变而缺乏有效的治疗药物。γ-氨基丁酸转运体-1（GAT-1）在紫杉醇诱导的神经性疼痛（PINP）期间，其在脑和脊髓中的表达增加，可能是治疗PINP的潜在靶点。因此，我们的目的是评估全身给予GAT-1抑制剂是否能改善PINP。
记录雌性BALB/c小鼠在腹腔注射紫杉醇、其溶媒和/或选择性GAT-1抑制剂NO-711之前和之后对热刺激（热板试验；55°C）和冷刺激（冷板试验；4°C）的反应潜伏期。使用转棒试验以4 rpm的恒定速度或在5分钟内从4 rpm加速到40 rpm的加速模式评估NO-711对运动协调性的影响。
在药物治疗后第7天，紫杉醇与3 mg/kg的NO-711联合给药可预防紫杉醇诱导的热痛觉过敏和冷痛觉异常的发生。在已建立紫杉醇诱导的热痛觉过敏和冷痛觉异常的小鼠中，3 mg/kg的NO-711产生的抗痛觉过敏活性长达1小时，抗痛觉异常活性长达2小时。3 mg/kg剂量的NO-711未观察到运动功能缺陷，而较高剂量5 mg/kg会导致运动障碍，并降低在4 rpm恒定速度下在转棒上花费的平均时间。然而，在5分钟内从4 rpm加速到40 rpm的转棒加速模式下，3 mg/kg的NO-711会导致长达1小时的运动障碍，但在2小时时已恢复。
这些结果表明，全身给予GAT-1抑制剂NO-711对紫杉醇诱导的热痛觉过敏和冷痛觉异常具有预防和治疗作用。NO-711的抗痛觉异常作用而非抗痛觉过敏作用与其运动障碍/镇静特性无关。因此，低剂量的GAT-1抑制剂通过适当的剂量滴定以减少运动障碍/镇静副作用，可能对PINP的预防和治疗有用。
