title: 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.affiliation: Department of Anesthesiology, Osaka Medical College, Takatsuki 569-8686, Japan. ane053@poh.osaka-med.ac.jp
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Miyazaki
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Minami
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mizuma
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Kanazawa
authors.forename: Hisashi
authors.initials: H
authors.lastname: Doi
authors.forename: Shinji
authors.initials: S
authors.lastname: Matsumura
authors.forename: Jingshan
authors.initials: J
authors.lastname: Lu
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Onoe
authors.forename: Kyoji
authors.initials: K
authors.lastname: Furuta
authors.forename: Masaaki
authors.initials: M
authors.lastname: Suzuki
authors.forename: Seiji
authors.initials: S
authors.lastname: Ito
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000166:cytology; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D007608:Kainic Acid / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000737:chemistry; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism
chemical_list: D002118:Calcium; D007608:Kainic Acid; D018092:Kainic Acid Receptors; C527035:(2S,3R,4R)-3-carboxymethyl-4-(phenylthio)pyrrolidine-2-carboxylic acid; C051743:acromelic acid A