Elucidation of Mechanism of Pain Transmission by Gene Targeting

长期的炎症和神经损伤常常导致慢性疼痛，这样有害的刺激引起痛觉过敏，无害的触觉刺激引起疼痛（异常性疼痛）。随着分子生物学的出现，P物质和谷氨酸已被证明与急性疼痛和痛觉过敏有关，但与异常性疼痛有关的因素仍不清楚。我们发现鞘内给药前列腺素E_2可引起清醒小鼠的异常性疼痛，并建立了体内异常性疼痛模型。近年来，我们通过受体激动剂和拮抗剂从药理学上阐明了异位性疼痛的机制。在此，我们将该模型应用于缺乏脂钙素型PGD合酶（L-PGDS）的小鼠，得到以下结果：PGD_2和PGE_2在L-PGDS-/-小鼠和野生型小鼠中均可引起痛觉过敏，而PGE_2在L-PGDS-/-小鼠中未引起异常痛觉。同时给药一定剂量的PGD_2和PGE_2可引起L-PGDS-/- m小鼠异常性疼痛，其程度与野生型小鼠相同。这些结果表明，POD_2对pge_2诱导的异常性疼痛的诱导至关重要。由于PGD_2在pg水平上阻断pge_2诱导的异位性疼痛，这些pds -/-敲除小鼠的实验首次证明PGD_2可能双相调节pge_2诱导的异位性疼痛的诱导。此外，抑制氨基酸GABA被认为介导PGD_2的作用。目前，缺乏其他PG合成酶和PG受体的敲除小鼠的实验正在研究中。直到最近，人们普遍认为pg作用于外周神经系统的疼痛传递，而阿片类物质作用于中枢神经系统。在发育技术和基因定位技术的帮助下，我们已经证明POs和阿片类药物在分子水平上诱导异位性疼痛中起重要作用。我们最近成功地从大脑中分离出一种新的肽nocistatin，其受体的克隆和表征正在进行中。少

Prolonged inflammation and nerve injury often lead to chronic pain such that noxious stimuli evoke hyperalgesia and innocuous tactile stimuli evoke pain (allodynia). With the advent of molecular biology, substance P and glutamate have been shown to be involved in acute pain and hyperalgesia, but a factor(s) involving allodynia had remained to be known. We found that intrathecal administration of prostaglandin E_2 induced allodynia in conscious mice and established an in vivo allodynia model. These several years, we have pharmacologically elucidated the mechanism of allodynia by use of receptor agonists and antagonists. Here, we applied this model to mice lacking lipocalin-type PGD synthase (L-PGDS) and obtained following results.While hyperalgesia induced by PGD_2 and PGE_2 was observed in L-PGDS-/- mice as well as wild-type mice, PGE_2-induced allodynia was not observed in L-PGDS-/-. Simultaneous administration of a femtogram amount of PGD_2 with PGE_2 induced allodynia in L-PGDS-/- m … More ice to the same extent as in wild-type mice. These results demonstrate that POD_2 is essential for induction of PGE_2-induced allodynia. Because PGD_2 blocked PGE_2-induced allodynia at a pg level, these experiments with PGDS-/- knockout mice first demonstrate that PGD_2 may regulate the induction of PGE_2-induced allodynia biphasically. Furthermore, the inhibitory amino acid GABA was suggested to mediate the action of PGD_2. At present experiments with knockout mice lacking other PG synthases and PG receptors are under investigation. Until recently, it was generally accepted that PGs act on pain transmission in the periphery and that opioids act, in the central nervous system. With the aid of developmental technology and genetargeting techniques, we have shown that both POs and opioids play important roles in induction of allodynia at the molecular level. We have recently succeeded in isolation of a novel peptide nocistatin from the brain and the cloning and characterization of its receptor are in progress. Less