Acute and late effects on induction of allodynia by acromelic acid, a mushroom poison related structurally to kainic acid.
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 x kg(-1) to 0.5 pg x kg(-1) and the maximum effect was observed at 50 fg x kg(-1). On the other hand, ACRO-B induced allodynia in a dose-dependent manner from 50 pg x kg(-1) to 50 ng x kg(-1). 3. N-methyl-d-aspartate (NMDA) receptor antagonists and Joro spider toxin, a Ca(2+)-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 x kg(-1)) and ACRO-B (50 ng x kg(-1)) was selectively lost 1 week after i.t. injection of a sublethal dose of ACRO-A (50 ng x kg(-1)) or ACRO-B (250 ng x kg(-1)). Higher doses of ACRO-A, however, could evoke allodynia dose-dependently from 50 pg x kg(-1) to 500 ng x kg(-1) in the ACRO-A-treated mice. The allodynia induced by ACRO-A (500 ng x 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 [Ca(2+)](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. 6. Taken together, these results demonstrate the stereospecificity of ACRO for the induction of allodynia and suggest the presence of a receptor specific to ACRO.
Minami
Toshiaki
T
Department of Anesthesiology, Osaka Medical College, Takatsuki 569-8686, Japan.
Matsumura
Shinji
S
Nishizawa
Mikio
M
Sasaguri
Yasuyuki
Y
Hamanaka
Nobuyuki
N
Ito
Seiji
S
D000818:Animals; D001487:Basidiomycota / Q000737:chemistry / Q000302:isolation & purification; D001569:Benzodiazepines / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005971:Glutamates / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000008:administration & dosage / Q000009:adverse effects*; D007211:Indoles / Q000494:pharmacology; D007278:Injections, Spinal; D007564:Japan; D007608:Kainic Acid / Q000008:administration & dosage / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000737:chemistry; D008161:Lumbosacral Region / Q000293:injuries / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009145:Mushroom Poisoning / Q000150:complications; D010091:Oximes / Q000494:pharmacology; D010146:Pain / Q000139:chemically induced* / Q000150:complications / Q000517:prevention & control; D011810:Quinoxalines / Q000494:pharmacology; D018091:Receptors, AMPA / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D016194:Receptors, N-Methyl-D-Aspartate / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D013111:Spider Venoms / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013997:Time Factors; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D005971:Glutamates; D006571:Heterocyclic Compounds; D007211:Indoles; C044936:JSTX spider toxin; D010091:Oximes; D011810:Quinoxalines; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D013111:Spider Venoms; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D001569:Benzodiazepines; C084273:5-nitro-6,7,8,9-tetrahydrobenzo(G)indole-2,3-dione-3-oxime; C046105:4-methylglutamic acid; C061627:Nerisopam; D016291:Dizocilpine Maleate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C051743:acromelic acid A; D007608:Kainic Acid; C438458:acromelic acid B