Selective NMDA NR2B antagonists induce antinociception without motor dysfunction: correlation with restricted localisation of NR2B subunit in dorsal horn.
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.
Boyce
S
S
Merck Sharp Laboratory, Neuroscience Research Centre, Harlow, UK. susan_boyce@merck.com
Wyatt
A
A
Webb
J K
JK
O'Donnell
R
R
Mason
G
G
Rigby
M
M
Sirinathsinghji
D
D
Hill
R G
RG
Rupniak
N M
NM
D000085:Acetates / Q000494:pharmacology; D000588:Amines; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D003509:Cyclohexanecarboxylic Acids; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D000077206:Gabapentin; D006930:Hyperalgesia / Q000188:drug therapy*; D000077213:Lamotrigine; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D010147:Pain Measurement / Q000187:drug effects*; D010636:Phenols / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000235:genetics; D013116:Spinal Cord / Q000166:cytology; D014227:Triazines / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid
D000085:Acetates; D000588:Amines; D000927:Anticonvulsants; D003509:Cyclohexanecarboxylic Acids; D018691:Excitatory Amino Acid Antagonists; D010636:Phenols; D010880:Piperidines; D011760:Pyrrolidinones; D016194:Receptors, N-Methyl-D-Aspartate; C109643:Ro 25-6981; D014227:Triazines; C084173:L 687414; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D016291:Dizocilpine Maleate; C095106:traxoprodil mesylate; C010739:ifenprodil; D000077213:Lamotrigine