The action site of the synthetic kainoid (2S,3R,4R)-3-carboxymethyl-4-(4-methylp henylthio) pyrrolidine-2-carboxylic acid (PSPA-4), an analogue of Japanese mushroom poison acromelic acid, for allodynia (tactile pain)
The action site of the synthetic kainoid (2S,3R,4R)-3-carboxymethyl-4-(4-methylp henylthio) pyrrolidine-2-carboxylic acid (PSPA-4), an analogue of Japanese mushroom poison acromelic acid, for allodynia (tactile pain)
复制标题
合成类红蛋白 (2S,3R,4R)-3-羧甲基-4-(4-甲基苯硫基)吡咯烷-2-羧酸 (PSPA-4) 的作用位点，它是日本蘑菇毒蕈酸的类似物，用于治疗异常性疼痛
DOI：
10.1016/j.ejphar.2012.10.023
复制
发表时间：
2012
期刊：
影响因子：
5
通讯作者：
Suzuki M and Ito S
中科院分区：
文献类型：
--
作者：
Miyazaki S;Minami T;Mizuma H;Kanazawa;M;Doi H;Matsumura S;Lu J;Onoe H;Furuta K;Suzuki M and Ito S
我们以前证明鞘内（i.t.）给予丙烯酸A（Acro-A）在小鼠中诱导异常性疼痛，同时给予（2S，3R，4 R）-3-羧甲基-4-（苯硫基）吡咯烷-2-羧酸（PSPA-1，Acro-A类似物）减轻Acro-A诱导的异常性疼痛。为了阐明PSPA-1的作用机制，我们将甲基连接到PSPA-1上，合成了（2S，3R，4 R）-3-羧甲基-4-（4-甲基苯硫基）吡咯烷-2-羧酸（PSPA-4）和[11 C]PSPA-4，并对其进行了行为学和放射自显影研究。虽然PSPA-4以1至10 fg/小鼠的剂量依赖性方式抑制Acro-A诱导的异常性疼痛，但PSPA-4本身在10至100 pg/小鼠诱导异常性疼痛。在体外放射自显影中，[11 C]PSPA-4特异性结合于大鼠脑和脊髓，并且该结合被PSPA-1和红藻氨酸显著取代，但不被AMPA和NMDA、AMPA和红藻氨酸受体的拮抗剂取代。相反，[3 H]红藻氨酸特异性结合到大鼠脑和脊髓背角，并且该结合被PSPA-1和PSPA-4显著取代。AMPA/红藻氨酸盐拮抗剂GYKI 53655可阻断PSPA-4诱导的痛觉超敏反应，但红藻氨酸盐拮抗剂NS 102和UBP 296不能阻断。PSPA-4可使27.9%的培养背根神经节神经元内Ca ~（2+）浓度升高，明显高于红藻氨酸的10.9%。总之，这些结果表明，PSPA-4通过与已知红藻氨酸拮抗剂不同的结合位点在低剂量下减弱Acro-A诱导的异常性疼痛，在高剂量下诱导异常性疼痛。放射性标记的PSPA-4的开发将使我们能够促进不仅对Acro-A的作用机制的理解，而且对外周和中枢神经系统的疼痛传递的理解。
We previously demonstrated that intrathecal (i.t.) administration of acromelic acid A (Acro-A) induced allodynia in mice and that simultaneous administration of (2S,3R,4R)-3-carboxymethyl-4-(phenylthio)pyrrolidine-2-carboxylic acid (PSPA-1), an Acro-A analogue, attenuated the Acro-A-induced allodynia. To clarify a mechanism of PSPA-1, we attached methyl radical to PSPA-1 and synthesized (2S,3R,4R)-3-carboxymethyl-4-(4-methylphenylthio) pyrrolidine-2-carboxylic acid (PSPA-4) and [11C]PSPA-4 for behavioral and autoradiography studies. Although PSPA-4 inhibited the Acro-A-induced allodynia in a dose-dependent manner from 1 to 10fg/mouse, PSPA-4 itself induced allodynia at 10 to 100pg/mouse. In vitro autoradiography, [11C]PSPA-4 was specifically bound to the rat brain and spinal cord, and the binding was significantly displaced by PSPA-1 and kainic acid, but not by AMPA and antagonists of NMDA, AMPA and kainate receptors. Conversely, [3H]kainate was specifically bound to the rat brain and the dorsal horn of spinal cord, and the binding was significantly displaced by PSPA-1 and PSPA-4. The PSPA-4-induced allodynia was blocked by the AMPA/kainate antagonist GYKI53655, but not by kainate antagonists NS102 and UBP296. PSPA-4 increased intracellular Ca2+concentration in 27.9% of cultured dorsal root ganglion neurons responding to glutamate, much higher than kainate in 10.9% of them. Taken together, these results suggest that PSPA-4 attenuated the Acro-A-induced allodynia at low doses and induced allodynia at high doses via a binding site different from known kainate antagonists. The development of a radio-labeled PSPA-4 will enable us to promote the understanding of the action mechanism not only of Acro-A, but also of pain transmission in the periphery and central nervous system.