Eguchi N, Minami T, Shirafuji N, Kanaoka Y, Tanaka T, Nagata A, Yoshida N, Urade Y, Ito S, Hayaishi O
Precursory Research for Embryonic Science and Technology, Japan Science and Technology Corporation, Department of Morphological Brain Science, Faculty of Medicine, Kyoto University, Sakyo, Kyoto 606-8315, Japan.
Proc Natl Acad Sci U S A. 1999 Jan 19;96(2):726-30. doi: 10.1073/pnas.96.2.726.
Prostaglandin (PG) D2 is the most abundant prostanoid produced in the central nervous system of mammals and has been implicated in the modulation of neural functions such as sleep induction, nociception, regulation of body temperature, and odor responses. We generated gene-knockout mice for lipocalin-type PGD2 synthase (L-PGDS) and found that the intrathecal administration of PGE2, an endogenous pain-producing substance, failed to elicit allodynia (touch-evoked pain), which is one typical phenomenon of neuropathic pain, whereas it evoked thermal hyperalgesia, in L-PGDS-/- mice. We also found that the allodynic response induced by the gamma-aminobutyric acid (GABA)A receptor antagonist bicuculline was selectively abolished in the L-PGDS-/- mice, among excitatory and inhibitory agents that induced allodynia in wild-type mice. Interestingly, simultaneous injection of a femtogram amount of PGD2 with PGE2 or bicuculline induced allodynia in L-PGDS-/- mice to the same extent as in wild-type mice. The PGE2- or bicuculline-evoked allodynia in wild-type and in PGD2-supplemented L-PGDS-/- mice was blocked by a PGD2 receptor antagonist given in a femtogram amount. These results reveal that endogenous PGD2 is essential for both PGE2- and bicuculline-induced allodynia.
前列腺素（PG）D2是哺乳动物中枢神经系统中产生的最丰富的类前列腺素，并且与神经功能的调节有关，如诱导睡眠、痛觉感受、体温调节和气味反应。我们构建了脂质运载蛋白型PGD2合酶（L-PGDS）基因敲除小鼠，发现鞘内注射内源性致痛物质前列腺素E2（PGE2）未能引发机械性异常疼痛（触摸诱发疼痛），这是神经性疼痛的一种典型现象，而在L-PGDS基因敲除小鼠中它却诱发了热痛觉过敏。我们还发现，在野生型小鼠中能诱发机械性异常疼痛的兴奋性和抑制性药物中，γ-氨基丁酸（GABA）A受体拮抗剂荷包牡丹碱诱导的机械性异常疼痛反应在L-PGDS基因敲除小鼠中被选择性消除。有趣的是，同时向L-PGDS基因敲除小鼠注射飞克量的PGD2与PGE2或荷包牡丹碱，诱发的机械性异常疼痛程度与野生型小鼠相同。飞克量的PGD2受体拮抗剂可阻断野生型小鼠以及补充了PGD2的L-PGDS基因敲除小鼠中PGE2或荷包牡丹碱诱发的机械性异常疼痛。这些结果表明，内源性PGD2对于PGE2和荷包牡丹碱诱导的机械性异常疼痛均至关重要。
