Selective NMDA NR2B antagonists induce antinociception without motor dysfunction: correlation with restricted localisation of NR2B subunit in dorsal horn

Neuropharmacology. 1999 May;38(5):611-23. doi: 10.1016/s0028-3908(98)00218-4.


The present study investigated the regional distribution of the N-methyl-D-aspartate (NMDA) receptor containing the NR2B subunit protein in rat lumbar spinal cord and examined whether selective NR2B antagonists would exhibit antinociception with reduced side-effect liability than subtype non-selective NMDA antagonists and anticonvulsants. Immunocytochemical studies showed the NR2B subunit had a restricted distribution, with moderate labelling of fibres in laminas I and II of the dorsal horn suggesting a presynaptic location on primary afferent fibers and possible involvement in pain transmission. In the in vivo studies, the NMDA/glycine antagonists (MK-801, 0.02-1 mg/kg i.p., L-687,414 10-300 mg/kg i.p., and L-701,324 1-10 mg/kg i.p.) and the anticonvulsant, gabapentin (10-500 mg/kg p.o.), induced rotarod deficits at antinociceptive doses. In contrast, the selective NR2B antagonists, (+/-)-CP-101,606 (1-100 mg/kg p.o.) and (+/-)-Ro 25-6981 (3-100 mg/kg i.p.) showed a significant dose window. (+/-)-CP-101,606 caused no motor impairment or stimulation in rats at doses up to 100 mg/kg p.o., which is far in excess of those inhibiting allodynia in neuropathic rats (ID50 4.1 mg/kg, p.o.). (+/-)-Ro 25-6981 also showed a significant separation (ID50 allodynia 3.8 mg/kg, i.p.), however, some disruption of rotarod performance was observed at 100 mg/kg. The anticonvulsant lamotrigine (3-500 mg/kg p.o.) also showed a good dose window. These findings demonstrate that NR2B antagonists may have clinical utility for the treatment of neuropathic and other pain conditions in man with a reduced side-effect profile than existing NMDA antagonists.

MeSH terms

  • Acetates / pharmacology
  • Amines*
  • Animals
  • Anticonvulsants / pharmacology
  • Cyclohexanecarboxylic Acids*
  • Dizocilpine Maleate / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Excitatory Amino Acid Antagonists / therapeutic use*
  • Gabapentin
  • Hyperalgesia / drug therapy*
  • Lamotrigine
  • Male
  • Motor Activity / drug effects*
  • Pain Measurement / drug effects*
  • Phenols / pharmacology
  • Piperidines / pharmacology
  • Pyrrolidinones / pharmacology
  • Rabbits
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Spinal Cord / cytology
  • Triazines / pharmacology
  • gamma-Aminobutyric Acid*


  • Acetates
  • Amines
  • Anticonvulsants
  • Cyclohexanecarboxylic Acids
  • Excitatory Amino Acid Antagonists
  • Phenols
  • Piperidines
  • Pyrrolidinones
  • Receptors, N-Methyl-D-Aspartate
  • Ro 25-6981
  • Triazines
  • L 687414
  • gamma-Aminobutyric Acid
  • Gabapentin
  • Dizocilpine Maleate
  • traxoprodil mesylate
  • ifenprodil
  • Lamotrigine