Acute and late effects on induction of allodynia by acromelic acid, a mushroom poison related structurally to kainic acid
Acute and late effects on induction of allodynia by acromelic acid, a mushroom poison related structurally to kainic acid
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DOI：
10.1038/sj.bjp.0705834
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发表时间：
2004-06-01
影响因子：
7.3
通讯作者：
Ito, S
中科院分区：
文献类型：
--
作者：
Minami, T;Matsumura, S;Ito, S
1已知摄入毒蘑菇Clitocybe acromelevis会导致四肢严重的触觉疼痛（异常性疼痛）持续一个月，而从蘑菇中分离出的红藻氨酸类似物acromelic acid（ACRO）在全身或鞘内注射时会对大鼠下脊髓的中间神经元产生选择性损伤。由于ACRO有两种异构体，ACRO-A和ACRO-B，在这里，我们研究了它们对诱发异常性疼痛的急性和晚期效应。2鞘内注射ACRO-A和ACRO-B通过注射后5分钟的第一次刺激引起明显的异常性疼痛，持续了50分钟的实验期。ACRO-A对诱发异常性疼痛的急性效应的剂量依赖性显示出从50 ag kg（-1）至0.5 pg kg-1的钟形模式，在50 fg kg-1时观察到最大效应。ACRO-B在50 pg kg ~（-1）~ 50 ng kg ~（-1）范围内呈剂量依赖性诱发痛敏。3 N-甲基-D-天冬氨酸（NMDA）受体拮抗剂和一种Ca ~（2+）可透过的AMPA受体拮抗剂Joro蜘蛛毒素可抑制ACRO-A诱发的痛敏，而ACRO-B则无此作用。然而，其他AMPA/红藻氨酸拮抗剂不影响ACRO诱导的异常性疼痛。4尽管在ACRO-A处理的小鼠的脊髓中没有观察到神经元损伤，但在i.t.注射亚致死剂量的ACRO-A（50 ng kg-1）或ACRO-B（250 ng kg-1）。然而，在ACRO-A治疗的小鼠中，较高剂量的ACRO-A可以剂量依赖性地诱发从50 pg kg-1至500 ng kg-1的异常性疼痛。Joro蜘蛛毒素或NMDA受体拮抗剂均不能抑制ACRO-A（500 ng kg-1）诱导的异常性疼痛。ACRO-A诱发的迟发性痛觉超敏的这些特性与ACRO-B诱发的急性痛觉超敏的特性非常相似。5 ACRO-A可增加脊髓深层的[Ca ~（2+）]（i），而不是浅层。这种增加没有被AMPA偏好拮抗剂GYKI 52466和Joro蜘蛛毒素阻断。总之，这些结果证明了ACRO诱导异常性疼痛的立体特异性，并表明存在对ACRO特异的受体。英国药理学杂志（2004）。
1 Ingestion of a poisonous mushroom Clitocybe acromelalga is known to cause severe tactile pain (allodynia) in the extremities for a month and acromelic acid (ACRO), a kainate analogue isolated from the mushroom, produces selective damage of interneurons of the rat lower spinal cord when injected either systemically or intrathecally. Since ACRO has two isomers, ACRO-A and ACRO-B, here we examined their acute and late effects on induction of allodynia.2 Intrathecal administration of ACRO-A and ACRO-B provoked marked allodynia by the first stimulus 5 min after injection, which lasted over the 50-min experimental period. Dose-dependency of the acute effect of ACRO-A on induction of allodynia showed a bell-shaped pattern from 50 ag kg(-1) to 0.5 pg kg-1 and the maximum effect was observed at 50 fg kg-1. On the other hand, ACRO-Binduced allodynia in a dose-dependent manner from 50 pg kg-1 to 50 ng kg-1.3 N-methyl-D-aspartate (NMDA) receptor antagonists and Joro spider toxin, a Ca2+-permeable AMPA receptor antagonist, inhibited the allodynia induced by ACRO-A, but not by ACRO-B. However, other AMPA/kainate antagonists did not affect the allodynia induced by ACRO.4 Whereas no neuronal damage was observed in the spinal cord in ACRO-A-treated mice, induction of allodynia by ACRO-A (50 fg kg-1) and ACRO-B (50 ng kg-1) was selectively lost 1 week after i.t. injection of a sublethal dose of ACRO-A (50 ng kg-1) or ACRO-B (250 ng kg-1). Higher doses of ACRO-A, however, could evoke allodynia dose-dependently from 50 pg kg-1 to 500 ng kg-1 in the ACRO-A-treated mice. The allodynia induced by ACRO-A (500 ng kg-1) was not inhibited by Joro spider toxin or NMDA receptor antagonists. These properties of the late allodynia induced by ACRO-A were quite similar to those of the acute allodynia induced by ACRO-B.5 ACRO-A could increase ([Ca2+])(i) in the deeper laminae, rather than in the superficial laminae, of the spinal cord. This increase was not blocked by the AMPA-preferring antagonist GYKI52466 and Joro spider toxin.AP6 Taken together, these results demonstrate the stereospecificity of ACRO for the induction of allodynia and suggest the presence of a receptor specific to ACRO. British Journal of Pharmacology (2004).