Intrathecal administration of AS1928370, a transient receptor potential vanilloid 1 antagonist, attenuates mechanical allodynia in a mouse model of neuropathic pain.
Intrathecal administration of AS1928370, a transient receptor potential vanilloid 1 antagonist, attenuates mechanical allodynia in a mouse model of neuropathic pain.
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鞘内注射 AS1928370（一种瞬时受体电位香草酸 1 拮抗剂）可减轻神经性疼痛小鼠模型中的机械异常性疼痛。
DOI：
10.1248/bpb.34.1105
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发表时间：
2011
影响因子：
2
通讯作者：
N. Matsuoka
中科院分区：
文献类型：
--
作者：
T. Watabiki;T. Kiso;M. Tsukamoto;T. Aoki;N. Matsuoka
瞬时受体电位香草酸 1 (TRPV1) 主要在非髓鞘初级传入神经元的中枢和外周末梢表达。我们之前表明，AS1928370 是一种新型 TRPV1 拮抗剂，可以阻止配体诱导的激活，但不能阻止质子诱导的激活，可改善大鼠的神经性疼痛，而无热效应。在这项研究中，我们研究了它对小鼠的镇痛作用。 AS1928370在小鼠体内表现出良好的口服生物利用度和对大脑和脊髓的高渗透性。平均血浆与大脑和血浆与脊髓的比率分别为 4.3 和 3.5。在热板试验中，口服 AS1928370 进行预处理，剂量为 10-30 mg/kg（口服），可显着抑制辣椒素引起的急性疼痛和戒断反应。在较低的口服剂量（0.3-1.0 mg/kg）下，AS1928370 改善了接受脊神经结扎的小鼠的机械性异常性疼痛。鞘内注射 AS1928370（30 µg/体）也显着抑制机械性异常性疼痛。此外，AS1928370 口服剂量高达 30 mg/kg 时对运动活动没有影响。这些结果表明脊髓TRPV1在神经性疼痛的传递中具有重要作用，并且中枢神经系统（CNS）渗透性TRPV1受体拮抗剂AS1928370是治疗神经性疼痛的有希望的候选药物。
Transient receptor potential vanilloid 1 (TRPV1) is primarily expressed in central and peripheral terminals of non-myelinated primary afferent neurons. We previously showed that AS1928370, a novel TRPV1 antagonist that can prevent ligand-induced activation but not proton-induced activation, ameliorates neuropathic pain in rats without hyperthermic effect. In this study, we investigated its analgesic profile in mice. AS1928370 showed good oral bioavailability and high penetration into the brain and spinal cord in mice. The mean plasma-to-brain and plasma-to-spinal cord ratios were 4.3 and 3.5, respectively. Pretreatment with AS1928370 significantly suppressed both capsaicin-induced acute pain and withdrawal response in hot plate test at 10-30 mg/kg per os (p.o.). At lower oral doses (0.3-1.0 mg/kg), AS1928370 improved mechanical allodynia in mice undergoing spinal nerve ligation. Intrathecal administration of AS1928370 (30 µg/body) also significantly suppressed mechanical allodynia. In addition, AS1928370 showed no effect on locomotor activity up to 30 mg/kg p.o. These results suggest that spinal TRPV1 has an important role in the transmission of neuropathic pain and that the central nervous system (CNS) penetrant TRPV1 receptor antagonist AS1928370 is a promising candidate for treating neuropathic pain.