The action site of the synthetic kainoid (2S,3R,4R)-3-carboxymethyl-4-(4-methylphenylthio)pyrrolidine-2-carboxylic acid (PSPA-4), an analogue of Japanese mushroom poison acromelic acid, for allodynia (tactile pain).

Abstract

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 [(11)C]PSPA-4 for behavioral and autoradiography studies. Although PSPA-4 inhibited the Acro-A-induced allodynia in a dose-dependent manner from 1 to 10 fg/mouse, PSPA-4 itself induced allodynia at 10 to 100 pg/mouse. In vitro autoradiography, [(11)C]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, [(3)H]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 Ca(2+) 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.

• Authors: Shinichiro Miyazaki, Toshiaki Minami, Hiroshi Mizuma, Masakatsu Kanazawa, Hisashi Doi, Shinji Matsumura, Jingshan Lu, Hirotaka Onoe, Kyoji Furuta, Masaaki Suzuki, Seiji Ito
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 710 Issue 1-3 Pg. 120-7 (Jun 15 2013) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 23124023 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier B.V. All rights reserved.

Chemical References

• (2S,3R,4R)-3-carboxymethyl-4-(phenylthio)pyrrolidine-2-carboxylic acid
• Receptors, Kainic Acid
• acromelic acid A
• Kainic Acid
• Calcium

Topics

• Animals
• Brain (metabolism)
• Calcium (metabolism)
• Cells, Cultured
• Ganglia, Spinal (cytology)
• Hyperalgesia (chemically induced, drug therapy, metabolism)
• Kainic Acid (administration & dosage, analogs & derivatives, chemistry)
• Male
• Mice
• Neurons (drug effects, metabolism)
• Rats
• Rats, Wistar
• Receptors, Kainic Acid (antagonists & inhibitors, metabolism)
• Spinal Cord (metabolism)