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: Claudio Laurido, Alejandro Hernández, Teresa Pelissier, Luis Constandil
• Journal: TheScientificWorldJournal (ScientificWorldJournal) Vol. 2012 Pg. 279147 ( 2012) ISSN: 1537-744X [Electronic] United States
• PMID: 22536130 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• 3-hydroxyaspartic acid
• Aspartic Acid
• Serine
• Racemases and Epimerases
• serine racemase

Topics

• Animals
• Arthritis (drug therapy, pathology)
• Aspartic Acid (analogs & derivatives, pharmacology, therapeutic use)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Pain (drug therapy)
• Racemases and Epimerases (antagonists & inhibitors)
• Rats
• Serine (pharmacology)