title: Antinociceptive effect of rat D-serine racemase inhibitors, L-serine-O-sulfate, and L-erythro-3-hydroxyaspartate in an arthritic pain model.
abstract: N-methyl-D-aspartic acid receptor (NMDAr) activation requires the presence of D-serine, synthesized from L-serine by a pyridoxal 5'-phosphate-dependent serine racemase (SR). D-serine levels can be lowered by inhibiting the racemization of L-serine. L-serine-O-sulfate (LSOS) and L-erythro-3-hydroxyaspartate (LEHA), among others, have proven to be effective in reducing the D-serine levels in culture cells. It is tempting then to try these compounds in their effectiveness to decrease nociceptive levels in rat arthritic pain. We measured the C-reflex paradigm and wind-up potentiation in the presence of intrathecally injected LSOS (100 μg/10 μL) and LEHA (100 μg/10 μL) in normal and monoarthritic rats. Both compounds decreased the wind-up activity in normal and monoarthritic rats. Accordingly, all the antinociceptive effects were abolished when 300 μg/10 μL of D-serine were injected intrathecally. Since no in vivo results have been presented so far, this constitutes the first evidence that SR inhibitions lower the D-serine levels, thus decreasing the NMDAr activity and the consequent development and maintenance of chronic pain.
authors.affiliation: Laboratorio de Neurobiología, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago 9170022, Chile. claudio.laurido@usach.cl
authors.forename: Claudio
authors.initials: C
authors.lastname: Laurido
authors.forename: Alejandro
authors.initials: A
authors.lastname: Hernández
authors.forename: Teresa
authors.initials: T
authors.lastname: Pelissier
authors.forename: Luis
authors.initials: L
authors.lastname: Constandil
mesh_terms: D000818:Animals; D001168:Arthritis / Q000188:drug therapy* / Q000473:pathology; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D010146:Pain / Q000188:drug therapy*; D019998:Racemases and Epimerases / Q000037:antagonists & inhibitors*; D051381:Rats; D012694:Serine / Q000494:pharmacology*; D000099300:Serine Racemase
chemical_list: D001224:Aspartic Acid; D004791:Enzyme Inhibitors; D019998:Racemases and Epimerases; D012694:Serine; D000099300:Serine Racemase; C011274:3-hydroxyaspartic acid