神経障害性疼痛と線維筋痛症様モデルマウスにおけるLPA受容体を介する痛みメモリー機構

抄録

We have firstly demonstrated that LPA1 receptor signaling initiates the neuropathic pain and underlying mechanisms including dorsal root (DR) demyelination and up–regulation of Ca_vα2δ1 in dorsal root ganglion (DRG), which are supposedly related to allodynia and hyperalgesia, respectively. Since this report, we have accumulated the findings supporting this discovery. They are the findings that LPA is produced in the spinal dorsal root upon the partial ligation of sciatic nerves of mice, the LPA production is self–amplified through activations of LPA1 ⁄ 3 receptors and microglia. Thus produced LPA may go back to DR and DRG and cause abnormal pain behavior. All these mechanisms may develop the feed–forward amplification of abnormal pain mechanisms, or pain memory. On the analogy of this neuropathic pain, we tested the involvement of LPA1 receptor signaling in experimental fibromyalgia–like mouse models, such as intermittent psychological stress (IPS)–, intermittent cold stress– and repeated intramuscular injection of acid saline–induced models. The deficiency of LPA1 receptor completely lost the hyperalgesia in all these models. The repeated treatments with LPA1 antagonist AM966 completely cured the established pain in the IPS model. All these findings demonstrate that LPA1 signaling plays key roles in the development and maintenance of chronic pain.