Effects of low-affinity NMDA receptor channel blockers in two rat models of chronic pain.
In contrast to conventional opioid analgesics, antagonists acting at the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors are capable of suppressing pain-related phenomena in chronic pain models while having little or no effect on acute nociception. One of the few clinically used NMDA receptor antagonists, memantine, differs from prototypic antagonists with psychotomimetic activity such as phencyclidine and (+)MK-801, in showing lower receptor affinity, faster unblocking kinetics and stronger voltage-dependency. Recently, a series of novel amino-alkyl-cyclohexanes was reported to interact with NMDA receptors in a manner similar to that of memantine. The present study aimed to evaluate the effects of these compounds as well as (+)MK-801 and memantine in two rat models of chronic pain and the rotarod test. Unlike (+)MK-801 and memantine, most of the tested compounds were inactive against tactile allodynia induced by sciatic nerve ligation. On the other hand, all tested drugs were found to inhibit formalin-induced grooming behavior-a model of chronic pain induction. In agreement with previous reports on the effects of NMDA receptor antagonists in similar assays, the late phase seemed to be inhibited to a greater extent than the early phase. For all tested compounds, inhibition of formalin-induced behaviors occurred at dose levels that were also producing significant motor deficits (rotarod test). These results confirm low efficacy of acute administration of NMDA receptor antagonists in the models of established pain states. Thus, studies on the prevention and management of chronic pain should focus on preemptive or long-term administration of NMDA receptor antagonists.
Medvedev
Ivan O
IO
Institute of Pharmacology, Pavlov Medical University, 6/8 Lev Tolstoy Street, 197089 St. Petersburg, Russia.
Malyshkin
Andrey A
AA
Belozertseva
Irina V
IV
Sukhotina
Irina A
IA
Sevostianova
Natalia Y
NY
Aliev
Kamal
K
Zvartau
Edwin E
EE
Parsons
Chris G
CG
Danysz
Wojciech
W
Bespalov
Anton Y
AY
D000818:Animals; D002908:Chronic Disease; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D005557:Formaldehyde; D006120:Grooming / Q000187:drug effects; D008026:Ligation; D008297:Male; D008559:Memantine / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement / Q000187:drug effects; D004856:Postural Balance / Q000187:drug effects; D018075:RNA, Complementary / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D012584:Sciatic Nerve / Q000502:physiology; D020426:Sciatic Neuropathy / Q000188:drug therapy / Q000523:psychology; D014981:Xenopus
D018691:Excitatory Amino Acid Antagonists; D018075:RNA, Complementary; D016194:Receptors, N-Methyl-D-Aspartate; D005557:Formaldehyde; D016291:Dizocilpine Maleate; D008559:Memantine