Ligands for peroxisome proliferaoractivated receptor as possible novel analgesic

虽然麻醉镇痛药具有较高的疗效，但由于医疗保险覆盖问题、副作用、滥用的可能性等原因，可能导致临床使用犹豫不决，患者生活质量下降。因此，非麻醉性镇痛药及其辅助剂的开发取得了长足的进展。我们关注神经炎症在神经性疼痛（NP）和顽固性疼痛中的参与，以及核受体过氧化物酶体增殖物激活受体γ (PPARγ)配体的抗炎症作用。我们研究了PPARγ在NP中的作用。我们以部分坐骨神经结扎（PSL）小鼠作为NP模型，因为它们出现了触觉异常性痛。PSL增加了SCN中pSTAT3 （Jak-STAT通路中的一种活化形式）、IL6和TNFα、炎症因子和PPARγ的表达。这些表达在PSL诱导的SCN募集的巨噬细胞中观察到。给药AG490、Jak-STAT通路抑制剂、il - 6和tnf - α中和抗体可抑制psl诱导的触觉异常性痛的发生。PPAR受体激动剂吡格列酮（一种治疗2型糖尿病的药物）可以减轻psl诱导的触觉异常性疼痛，这与psl诱导的SCN中pSTAT3、IL6和TNFα表达的增加的衰减有关。这些结果表明，炎症细胞因子的增加和由此产生的Jak-STAT通路的激活有助于psl诱导的小鼠触觉异常性痛的发展。研究结果对鉴定NP发育的新调控分子具有重要的学术意义。此外，通过提出吡格列酮是新型镇痛药的有希望的种子的可能性，可以预期社会，经济效果。

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.