Characterization of the glutamatergic system for induction and maintenance of allodynia.
Glutamate is the main excitatory neurotransmitter in the central nervous system and has been shown to be involved in spinal nociceptive processing. We previously demonstrated that intrathecal (i.t.) administration of prostaglandin (PG) E(2) and PGF(2 alpha) induced touch-evoked pain (allodynia) through the glutamatergic system by different mechanisms. In the present study, we characterized glutamate receptor subtypes and glutamate transporters involved in induction and maintenance of PGE(2)- and PGF(2 alpha)-evoked allodynia. In addition to PGE(2) and PGF(2 alpha), N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), but not kainate, induced allodynia. PGE(2)- and NMDA-induced allodynia were observed in NMDA receptor epsilon 4 (NR2D) subunit knockout (GluR epsilon 4(-/-)) mice, but not in epsilon 1 (NR2A) subunit knockout (GluR epsilon 1(-/-)) mice. Conversely, PGF(2 alpha)- and AMPA-induced allodynia were observed in GluR epsilon 1(-/-) mice, but not in GluR epsilon 4(-/-) mice. The induction of allodynia by PGE(2) and NMDA was abolished by the NMDA receptor epsilon 2 (NR2B) antagonist CP-101,606 and neonatal capsaicin treatment. PGF(2 alpha)- and AMPA-induced allodynia were not affected by CP-101,606 and by neonatal capsaicin treatment. On the other hand, the glutamate transporter blocker DL-threo-beta-benzyloxyaspartate (DL-TBOA) blocked all the allodynia induced by PGE(2), PGF(2 alpha), NMDA, and AMPA. These results demonstrate that there are two pathways for induction of allodynia mediated by the glutamatergic system and suggest that the glutamate transporter is essential for the induction and maintenance of allodynia.
Department of Anesthesiology, Osaka Medical College, Takatsuki 569-8686, Japan.
T
T
Minami
S
S
Matsumura
E
E
Okuda-Ashitaka
K
K
Shimamoto
K
K
Sakimura
M
M
Mishina
H
H
Mori
S
S
Ito
D018528:ATP-Binding Cassette Transporters / Q000187:drug effects / Q000378:metabolism; D027322:Amino Acid Transport System X-AG; D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism; D001224:Aspartic Acid / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology; D015237:Dinoprost / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016202:N-Methylaspartate / Q000494:pharmacology; D010146:Pain / Q000378:metabolism* / Q000503:physiopathology; D010147:Pain Measurement / Q000187:drug effects; D010812:Physical Stimulation; D020671:Posterior Horn Cells / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D017470:Receptors, Glutamate / Q000187:drug effects* / Q000378:metabolism; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D014110:Touch / Q000187:drug effects* / Q000502:physiology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D018528:ATP-Binding Cassette Transporters; D027322:Amino Acid Transport System X-AG; D018690:Excitatory Amino Acid Agonists; D017470:Receptors, Glutamate; C120673:benzyloxyaspartate; D001224:Aspartic Acid; D018698:Glutamic Acid; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D015237:Dinoprost; D015232:Dinoprostone; D002211:Capsaicin