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Ligands for peroxisome proliferaoractivated receptor as possible novel analgesic

过氧化物酶体增殖物激活受体的配体作为可能的新型镇痛剂

基本信息

批准号：
18613014
负责人：
SHIROH Kishioka
金额：
$ 2.52万
依托单位：
Wakayama Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18613014/
关键词：
PPARγ inflammatory cytokine neuropathic pain Jak-STAT 疼痛 PPAR 神経炎症サイトカイン

项目摘要

The problem on coverage of the medical insurance, the side effect, and the possibility of the abuse may cause the hesitation of clinical use and the decrease in patient's QOL, though narcotic analgesics show high effectiveness. Therefore, non-narcotic analgesics and the development of its adjuvant have been advanced so far. We paid attention to the participation of the neuroinflammation in neuropathic pain (NP), the intractable pain, and to the anti-inflammation action of ligands for peroxisome proliferator-activated receptor γ (PPARγ), the nuclear receptor. We examined the role of PPARγ in NP. Mice with partial sciatic nerve (SCN) ligation (PSL) were used as a model for NP, because tactile allodynia was developed in them. PSL increased the expression of pSTAT3, an activated form in the Jak-STAT pathway, IL6 and TNFα, inflammatory cytokines, and PPARγ in the SCN. Those expressions were observed in the macrophages recruited in the SCN with PSL. The development of PSL-induced tactile allodynia was inhibited by the administration of AG490, inhibitor of Jak-STAT pathway, and neutralizing antibodies against IL6 and TNFα. Administration of PPAR y agonist pioglitazon, a therapeutic agent for type 2 diabetes mellitus, alleviated PSL-induced tactile allodynia, associated by an attenuation of the PSL-induced increase in the expression of pSTAT3, IL6 and TNFα in the SCN. These results indicate that increased production of inflammatory cytokines and resultant activation of Jak-STAT pathway contribute to the development of PSL-induced tactile allodynia in mice. The research results have an academic significance in terms of identification of the novel molecules regulating NP development. In addition, a social, economical effect can be expected by presenting the possibility that pioglitazon is a promising seed for novel type of analgesics.

虽然麻醉性镇痛药具有较高的镇痛效果，但由于医疗保险的覆盖范围、副作用以及滥用的可能性等问题，导致临床用药的犹豫和患者生活质量的下降。因此，非麻醉性镇痛药及其辅助剂的开发取得了进展。近年来，神经炎症在神经病理性疼痛（neuropathic pain，NP）中的作用以及核受体过氧化物酶体增殖物激活受体γ（peroxisome proliferator-activated receptor γ，PPARγ）配体的抗炎作用受到广泛关注。我们研究了PPARγ在NP中的作用。部分坐骨神经（SCN）结扎（PSL）的小鼠被用作NP的模型，因为在它们中产生了触觉异常性疼痛。PSL增加SCN中pSTAT 3（Jak-STAT途径中的活化形式）、IL 6和TNFα、炎性细胞因子和PPARγ的表达。在具有PSL的SCN中募集的巨噬细胞中观察到这些表达。给予AG 490、Jak-STAT通路抑制剂和抗IL 6和TNFα的中和抗体可抑制PSL诱导的触觉异常性疼痛的发生。给予PPAR γ激动剂吡格列酮（一种2型糖尿病的治疗药物）可减轻PSM诱导的触觉异常性疼痛，这与PSM诱导的SCN中pSTAT 3、IL 6和TNFα表达增加的减弱有关。这些结果表明，炎症细胞因子的产生增加和Jak-STAT通路的激活有助于小鼠中的PSM诱导的触觉异常性疼痛的发展。研究结果对于鉴定新的NP发育调控分子具有重要的学术意义。此外，通过提出吡格列酮是一种有前途的新型镇痛药种子的可能性，可以预期的社会，经济效果。