Department of Pharmacology, Discovery Research, Suven Life Sciences Ltd, Serene Chambers, Road No 5, Avenue-7, Banjara Hills, Hyderabad, 500034, India.
Eur J Pharmacol. 2011 Oct 1;668(1-2):155-62. doi: 10.1016/j.ejphar.2011.06.032. Epub 2011 Jul 3.
Nerve injury, diabetes and cancer therapies are often associated with painful neuropathy. The mechanism underlying neuropathic pain remains poorly understood. The current therapies have limited efficacy and are associated with dose-limiting side effects. Compounds which act at nicotinic acetylcholine receptors have also been reported to show antinociceptive activity. Among those, tebanicline (ABT-594) a potent nicotinic acetylcholine receptor agonist demonstrated analgesic effects across a broad range of preclinical models of nociceptive and neuropathic pain. Another nicotinic acetylcholine receptor agonist, 5-[(1R,5S)-3,6-Diazabicyclo[3.2.0]heptan-6-yl]nicotinonitrile (A-366833) from the same group produced significant antinociceptive effects in writhing pain (abdominal constriction), acute thermal pain (hot box), persistent chemical pain (formalin induced) and neuropathic pain. In the present study, we have demonstrated the efficacy of A-366833 in rat models of chronic constriction injury, partial sciatic nerve ligation, spinal nerve ligation, diabetes, chemotherapy induced neuropathic pain and complete Freund's adjuvant induced inflammatory pain. A-366833 (1, 3 and 6 mg/kg) produced significant antihyperalgesic effects in partial sciatic nerve ligation, chronic constriction injury and spinal nerve ligation models. In the diabetic and chemotherapy induced neuropathic models compound exerted antinociceptive activity and reduction in the mechanical hyperalgesia was observed. A-366833 dose dependently attenuated mechanical hyperalgesia in complete Freund's adjuvant induced inflammatory pain model. These results demonstrated broad-spectrum antinociceptive properties of A-366833 in both neuropathic and inflammatory pain models.
神经损伤、糖尿病和癌症治疗通常与疼痛性神经病变有关。神经病理性疼痛的发病机制仍知之甚少。目前的治疗方法疗效有限，并伴有剂量限制的副作用。作用于烟碱型乙酰胆碱受体的化合物也被报道具有镇痛活性。其中，强力烟碱型乙酰胆碱受体激动剂替巴尼定（ABT-594）在多种疼痛和神经病理性疼痛的临床前模型中表现出镇痛作用。来自同一研究组的另一种烟碱型乙酰胆碱受体激动剂 5-[(1R,5S)-3,6-二氮杂双环[3.2.0]庚烷-6-基]烟酰胺腈（A-366833）在扭体疼痛（腹部收缩）、急性热痛（热箱）、持续性化学疼痛（福尔马林诱导）和神经病理性疼痛中产生了显著的镇痛作用。在本研究中，我们证明了 A-366833 在大鼠慢性缩窄性损伤、部分坐骨神经结扎、脊神经结扎、糖尿病、化疗诱导的神经病理性疼痛和完全弗氏佐剂诱导的炎症性疼痛模型中的疗效。A-366833（1、3 和 6mg/kg）在部分坐骨神经结扎、慢性缩窄性损伤和脊神经结扎模型中产生了显著的抗痛觉过敏作用。在糖尿病和化疗诱导的神经病理性模型中，该化合物表现出镇痛活性，并且观察到机械性痛觉过敏减轻。A-366833 剂量依赖性地减轻了完全弗氏佐剂诱导的炎症性疼痛模型中的机械性痛觉过敏。这些结果表明 A-366833 在神经病理性和炎症性疼痛模型中具有广谱的镇痛特性。
