Potentiation by DL-alpha-aminopimelate of the inhibitory action of a novel mGluR agonist (L-F2CCG-I) on monosynaptic excitation in the rat spinal cord.
1. Neuropharmacological actions of all the possible stereoisomers of 3',3'-difluoro-2-(carboxycyclopropyl)glycine (3',3'-difluoro-CCG) were compared with those of the corresponding 2-(carboxycyclopropyl)glycine (CCG) isomers in the isolated spinal cord of newborn rats. (2S,1'S,2'S)- and (2S,1'R,2'S)-2-(2-carboxy-3,3-difluorocyclopropyl)glycine (L-F2CCG-I and L-F2CCG-IV) were the most potent in causing depolarization, their threshold concentrations being approximately 1 microM. 2. The depolarization evoked by L-F2CCG-I (30 microM) was depressed by (+)-alpha-methyl-4-carboxyphenylglycine (MCPG, 1 mM (n=4)) to 17+/-3% of the control: this depolarizing action was not decreased by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 100 microM), and only slightly decreased by high concentrations of D-2-amino-5-phosphonopentanoic acid (D-AP5, 100 microM), suggesting that L-F2CCG-I activates mainly metabotropic glutamate receptors. 3. L-F2CCG-I preferentially depressed the monosynaptic component of the spinal reflex approximately 3 times more effectively than (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (L-CCG-I). The depressant action of L-F2CCG-I (0.2 microM-0.7 microM) on monosynaptic excitation was antagonized by (2S,1'S,2'S)-2-methyl-2-(carboxycyclopropyl)glycine (MCCG, 0.3 mM-1 mM) and (S)-2-amino-2-methyl-4-phosphonobutanoic acid (MAP4, 0.3 mM). 4. DL-alpha-aminopimelate (10 and 100 microM) selectively potentiated the depression of monosynaptic excitation caused by L-CCG-I (0.2 microM) and L-F2CCG-I (0.1 microM). The actions of (2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV) (50 nM-0.2 microM), L-2-amino-4-phosphonobutanoic acid (L-AP4) (0.3-1 microM), (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid ((1S,3R)-ACPD) (1-7 microM) and baclofen (0.1-0.7 microM) were unaffected by DL-alpha-aminopimelate. The threshold concentration for the potentiating actions of DL-alpha-aminopimelate was 3 microM. 5. The depolarization induced by quisqualate (3 microM, 10 s application) was increased to 115+/-2% and 137+/-5% of the control values during combined application of quisqualate with either 30 microM or 100 microM DL-alpha-aminopimelate, respectively. 6. Following the application and subsequent washout of L-F2CCG-I, DL-alpha-aminopimelate (3-100 microM) decreased the amplitude of the monosynaptic component of spinal reflexes in a concentration-dependent manner, indicating a 'priming' effect of L-F2CCG-I.
Saitoh
T
T
Department of Pharmacology, The Tokyo Metropolitan Institute of Medical Science, Japan.
Ishida
M
M
Shinozaki
H
H
D000600:Amino Acids, Dicarboxylic / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004357:Drug Synergism; D018690:Excitatory Amino Acid Agonists / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D010867:Pimelic Acids / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013116:Spinal Cord / Q000187:drug effects* / Q000502:physiology; D013237:Stereoisomerism; D013569:Synapses / Q000187:drug effects*
C111411:2-(2-carboxy-3,3-difluorocyclopropyl)glycine; D000600:Amino Acids, Dicarboxylic; D018690:Excitatory Amino Acid Agonists; D010867:Pimelic Acids; C009845:alpha-aminopimelic acid