Ligands for peroxisome proliferaoractivated receptor as possible novel analgesic

尽管麻醉性镇痛药表现出较高的疗效，但其医保覆盖范围、副作用和滥用的可能性等问题可能会导致临床使用的犹豫和患者生活质量的下降。因此，目前非麻醉性镇痛药及其佐剂的开发取得了很大进展。我们关注神经炎症在神经病理性疼痛(NP)和顽固性疼痛中的作用，以及核受体PPARγ(PPARγ)的抗炎作用。我们研究了PPARγ在NP中的作用。部分坐骨神经(SCN)结扎(PSL)小鼠出现触觉超敏，可作为NP的动物模型。PSL可增加JAK-STAT通路中的活化形式pSTAT3、IL-6和肿瘤坏死因子α、炎性细胞因子和PPARγ在SCN中的表达。在伴有PSL的SCN中募集的巨噬细胞中可观察到这些表达。JAK-STAT通路阻断剂AG490和抗IL-6和肿瘤坏死因子α中和抗体可抑制PSL诱发的触觉超敏。治疗2型糖尿病的PPAR-y激动剂吡格列酮可减轻PSL诱导的触觉超敏反应，其机制可能与抑制PSL诱导的突触核内pSTAT3、IL-6和肿瘤坏死因子α的表达有关。这些结果表明，炎性细胞因子的产生增加和Jak-STAT通路的激活有助于PSL诱导的小鼠触觉过敏症的发生。研究结果对识别调控NP发育的新分子具有一定的学术意义。此外，吡格列酮有可能成为新型止痛药的种子，具有良好的社会、经济效应。

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.