Ligands for peroxisome proliferaoractivated receptor as possible novel analgesic

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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.