Antiallodynic effects of NMDA glycine(B) antagonists in neuropathic pain: possible peripheral mechanisms.
NMDA receptors are implicated in central sensitisation underlying chronic pain, and NMDA antagonists have a potential for the treatment of neuropathic pain. Functional NMDA receptors are also present on primary afferents, where they may play a role in pro-nociceptive plasticity. The importance of this mechanism in neuropathic pain remains unclear. In the present work, we have compared in models of chronic pain the effects of NMDA antagonists at the glycine(B) site with different central access. L-701,324 (the centrally active antagonist) and 5,7-dichlorokynurenic acid (5,7-DCK, known to have limited central access) were tested after systemic administration in rats in the formalin test and in two models of neuropathic pain. The ability of these compounds to exert central actions (sedation, ataxia) was tested in the open field locomotion test; central NMDA antagonism in vivo was tested in anaesthetised rats on responses of spinal cord neurones to iontophoretic NMDA. Both L-701,324 (2.15-21.5 mg/kg i.p.) and 5,7-DCK (10-46.4 mg/kg i.v.) dose-dependently inhibited Phase II of formalin-evoked behaviour. Likewise, both compounds reversed cold allodynia in the chronic constriction injury model and tactile allodynia in animals with spinal nerve ligation. However, only L-701,324 was able to inhibit neuronal responses to NMDA in the antihyperalgesic dose range; 5,7-DCK was inactive on NMDA responses up to 46.4 mg/kg i.v. or 68.1 mg/kg i.p. Consistent with the lack of inhibition of central NMDA-evoked activity, 5,7-DCK did not alter spontaneous behaviour in the open field test, whereas it was significantly inhibited by L-701,324. Thus, peripheral NMDA receptors may substantially contribute to the efficacy of NMDA antagonists in neuropathic pain.
Christoph
Thomas
T
Department of Pharmacology, Grünenthal GmbH R&D, Zieglerstr. 6, 52078 Aachen, Germany.
Reissmüller
Elke
E
Schiene
Klaus
K
Englberger
Werner
W
Chizh
Boris A
BA
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D003251:Constriction, Pathologic / Q000150:complications; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004347:Drug Interactions; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage*; D007736:Kynurenic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives*; D008026:Ligation / Q000379:methods; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D009437:Neuralgia / Q000188:drug therapy* / Q000209:etiology; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology; D010147:Pain Measurement / Q000379:methods; D015363:Quinolones / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000166:cytology; D013127:Spinal Nerves / Q000293:injuries / Q000503:physiopathology; D013997:Time Factors
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D015363:Quinolones; D016202:N-Methylaspartate; D007736:Kynurenic Acid; C094635:L 701324; C066192:5,7-dichlorokynurenic acid