title: 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.affiliation: Department of Pharmacology, Grünenthal GmbH Research Centre, Zieglerstrasse 6, 52078 Aachen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Christoph
authors.forename: Klaus
authors.initials: K
authors.lastname: Schiene
authors.forename: Werner
authors.initials: W
authors.lastname: Englberger
authors.forename: Chris G
authors.initials: CG
authors.lastname: Parsons
authors.forename: Boris A
authors.initials: BA
authors.lastname: Chizh
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D003080:Cold Temperature; D003251:Constriction, Pathologic / Q000150:complications; D018690:Excitatory Amino Acid Agonists / Q000008:administration & dosage / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005283:Fentanyl / Q000494:pharmacology; D007478:Iontophoresis; D007649:Ketamine / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D016202:N-Methylaspartate / Q000008:administration & dosage / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D010523:Peripheral Nervous System Diseases / Q000150:complications*; D010793:Phthalazines / Q000494:pharmacology; D020671:Posterior Horn Cells / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D000701:Analgesics, Opioid; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C112266:MRZ 2-576; D010793:Phthalazines; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D007649:Ketamine; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D005283:Fentanyl