Muthuraman Arunachalam, Jaggi Amteshwar Singh, Singh Nirmal, Singh Dhandeep
Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala-147002, India.
Eur J Pharmacol. 2008 Jun 10;587(1-3):104-11. doi: 10.1016/j.ejphar.2008.03.042. Epub 2008 Apr 8.
The present study was designed to investigate the ameliorative effects of clinically available drugs, with Na+/Ca2+ and Na+/H+ exchange inhibitory actions, in chronic constriction injury and vincristine induced painful neuropathy in rats. Sciatic nerve ligation and vincristine treatment (50 microg/kg for 10 days) was employed to induce neuropathy in rats. Paw pressure, von Frey hair, acetone drop, and tail heat immersion tests were performed to assess degree of mechano-hyperalgesia, mechano-allodynia, cold chemical allodynia and spinal thermal sensation respectively. Axonal degeneration of sciatic nerve was assessed histopathologically. The levels of thio-barbituric acid reactive species, reduced glutathione, and total calcium were determined to assess biochemical alterations. Amiloride (15 mg/kg i.p.), Na+/Ca2+ and Na+/H+ exchange inhibitor, and pralidoxime (20 mg/kg i.p.), Na+/Ca2+ exchange inhibitor, were administered for 10 consecutive days starting from the day of surgery or vincristine administration. Sciatic nerve ligation and vincristine treatment resulted in significant axonal degeneration, development of mechano-hyperalgesia, mechano-allodynia, cold chemical allodynia and spinal heat hyperalgesia and also resulted in rise in thio-barbituric acid reactive species, total calcium and decrease in reduced glutathione levels. Administration of amiloride and pralidoxime attenuated chronic constriction injury and vincristine induced axonal degeneration and reduction of nociceptive threshold along with reduction in calcium levels and oxidative stress. The observed anti-nociceptive effects of amiloride and pralidoxime may possibly be attributed to inhibition of Na+/Ca2+ and Na+/H+ exchangers with subsequent decrease in Ca2+ ions and oxidative stress.
本研究旨在调查具有钠/钙和钠/氢交换抑制作用的临床可用药物对大鼠慢性压迫性损伤和长春新碱诱导的疼痛性神经病变的改善作用。采用坐骨神经结扎和长春新碱治疗（50微克/千克，持续10天）诱导大鼠神经病变。分别进行爪部压力、von Frey毛发、丙酮滴注和尾部热浸试验，以评估机械性痛觉过敏、机械性异常性疼痛、冷化学性异常性疼痛和脊髓热感觉的程度。通过组织病理学评估坐骨神经的轴突退变。测定硫代巴比妥酸反应性物质、还原型谷胱甘肽和总钙水平，以评估生化改变。从手术或长春新碱给药之日起连续10天给予氨氯地平（15毫克/千克，腹腔注射），钠/钙和钠/氢交换抑制剂，以及解磷定（20毫克/千克，腹腔注射），钠/钙交换抑制剂。坐骨神经结扎和长春新碱治疗导致明显的轴突退变、机械性痛觉过敏、机械性异常性疼痛、冷化学性异常性疼痛和脊髓热痛觉过敏的发展，还导致硫代巴比妥酸反应性物质、总钙升高以及还原型谷胱甘肽水平降低。给予氨氯地平和解磷定可减轻慢性压迫性损伤和长春新碱诱导的轴突退变以及痛觉阈值降低，同时降低钙水平和氧化应激。氨氯地平和解磷定观察到的抗伤害感受作用可能归因于对钠/钙和钠/氢交换体的抑制，随后钙离子和氧化应激减少。
