The antiallodynic effect of NMDA antagonists in neuropathic pain outlasts the duration of the in vivo NMDA antagonism.

Abstract

Clinical reports have described a long-lasting relief in neuropathic pain patients treated with NMDA receptor antagonists; it is unclear, however, what mediates this effect. In this work, we have used two NMDA antagonists of different class to investigate if the antiallodynic effects in a rat neuropathy model can outlast their in vivo NMDA antagonism. Both the uncompetitive NMDA antagonist ketamine and the glycine(B) antagonist MRZ 2/576 inhibited neuronal responses to iontophoretic NMDA in anaesthetised rats with the time course consistent with their known pharmacokinetics (t(1/2) approximately 10-12min, similar in control and nerve-injured rats). Surprisingly, the antiallodynic effects of the same doses of the NMDA antagonists in the neuropathic pain model were long-lasting (>3h with ketamine, >24h with MRZ 2/576). The effect of ketamine was further prolonged (>24h) when combined with a short-acting opioid, fentanyl, which only produced a short effect ( approximately 40min) when given alone. The duration of centrally mediated side effects of ketamine and MRZ 2/576 was short, similar to the in vivo NMDA antagonism. We speculate that NMDA receptor blockade may down-regulate the central sensitisation triggered by nerve injury, resulting in a long-lasting antiallodynic effect. Development of short-acting NMDA antagonists could represent a strategy for improving their tolerability.

• Authors: Thomas Christoph, Klaus Schiene, Werner Englberger, Chris G Parsons, Boris A Chizh
• Journal: Neuropharmacology (Neuropharmacology) Vol. 51 Issue 1 Pg. 12-7 (Jul 2006) ISSN: 0028-3908 [Print] England
• PMID: 16616769 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Analgesics, Opioid
• Excitatory Amino Acid Agonists
• Excitatory Amino Acid Antagonists
• MRZ 2-576
• Phthalazines
• Receptors, N-Methyl-D-Aspartate
• N-Methylaspartate
• Ketamine
• alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
• Fentanyl

Topics

• Analgesics, Opioid (pharmacology)
• Animals
• Cold Temperature
• Constriction, Pathologic (complications)
• Excitatory Amino Acid Agonists (administration & dosage, pharmacology)
• Excitatory Amino Acid Antagonists (pharmacology)
• Fentanyl (pharmacology)
• Iontophoresis
• Ketamine (pharmacology)
• Male
• Motor Activity (drug effects)
• N-Methylaspartate (administration & dosage, pharmacology)
• Pain (drug therapy, etiology)
• Peripheral Nervous System Diseases (complications)
• Phthalazines (pharmacology)
• Posterior Horn Cells (drug effects)
• Rats
• Rats, Sprague-Dawley
• Receptors, N-Methyl-D-Aspartate (antagonists & inhibitors)
• Spinal Cord (cytology, drug effects)
• alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (administration & dosage, pharmacology)