N-methyl-D-aspartate receptor-mediated changes in thermal nociception: allosteric modulation at glycine and polyamine recognition sites.
The effects of allosteric modulators of the N-methyl-D-aspartic acid receptor ion-channel complex on the nociceptive tail-flick reflex were studied in awake rats. Intrathecal administration of D-serine (100 fmol-1 mumol) but not L-serine or glycine to the lumbar spinal cord produced a facilitation of the tail-flick reflex at doses > or = 1 pmol (maximum at 0.5-1 min). Intrathecal pretreatment with the glycine modulatory site antagonist 7-chlorokynurenic acid (3 pmol) blocked both D-serine-produced and N-methyl-D-aspartate-produced facilitation of the tail-flick reflex. D-serine-produced facilitation was also blocked by intrathecal pretreatment with a N-methyl-D-aspartate receptor ion-channel blocker, MK 801 (100 fmol), or with an alternate substrate for nitric oxide synthase, NG-nitro-L-arginine-methyl ester (100 nmol). Intrathecal administration of spermine (0.01 nmol-3 mumol) produced biphasic effects on tail-flick latency accompanied by mechanical hyperesthesia and vocalization at greater doses. Spermine-produced facilitation (maximum with 0.01 nmol to 1 nmol at 1 min) was blocked by intrathecal pretreatment with MK 801 (100 fmol), NG-nitro-L-arginine-methyl ester (100 nmol) or the polyamine modulatory site antagonist, arcaine (10 nmol). Spermine-produced inhibition (maximum with 300 nmol at 2 min) was blocked by intrathecal administration of MK 801 (1 nmol). Intrathecal administration of the N-methyl-D-aspartate receptor antagonist, D-2-amino-5-phosphonopentanoic acid (1 nmol), blocked inhibition and uncovered a facilitation produced by 1 mumol spermine. In addition, spermine produced multi-stage motor effects (immediate- and late-onset). Intrathecal pretreatment with MK 801 (1 nmol) blocked only the immediate-onset motor effects while the late-onset motor effects were selectively blocked by pretreatment with the kappa opioid receptor antagonist, nor-binaltorphamine (200 nmol). Taken together, these data suggest that D-serine and spermine facilitate nociceptive transmission by positive allosteric modulation of the N-methyl-D-aspartate receptor ion-channel. Furthermore, activation of the N-methyl-D-aspartate receptor is also necessary to elicit the immediate-onset motor effects and inhibition of the tail-flick reflex produced by greater doses of spermine. Because kappa opioid receptors appear to be involved, the spermine-produced late-onset motor effects may involve endogenous dynorphin release.
Kolhekar
R
R
Department of Pharmacology, University of Iowa, Iowa City 52242.
Meller
S T
ST
Gebhart
G F
GF
D000494:Allosteric Regulation; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D006358:Hot Temperature; D007278:Injections, Spinal; D007473:Ion Channels / Q000187:drug effects; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D009619:Nociceptors / Q000187:drug effects*; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018009:Receptors, Glycine / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects*; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects*; D017473:Receptors, Opioid, kappa / Q000187:drug effects; D012694:Serine / Q000494:pharmacology; D013096:Spermine / Q000494:pharmacology
D007473:Ion Channels; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D017473:Receptors, Opioid, kappa; D013096:Spermine; D009569:Nitric Oxide; D012694:Serine; D001120:Arginine; D019331:NG-Nitroarginine Methyl Ester