Characterization of the role of spinal N-methyl-D-aspartate receptors in thermal nociception in the rat.
The effects of N-methyl-D-aspartate (100 amol-1 nmol) on the nociceptive tail-flick reflex were studied in awake rats. Lesser doses of N-methyl-D-aspartate (100 amol-10 pmol) administered intrathecally to the lumbar spinal cord produced a dose-dependent facilitation of the tail-flick reflex (maximum at 0.5-1 min). The greatest dose tested (1 nmol) inhibited the tail-flick reflex (maximum at 2-5 min) and produced a caudally directed scratching and biting behavior accompanied by vocalizations. Intrathecal pretreatment with the N-methyl-D-aspartate receptor antagonist, D-2-amino-5-phosphonovaleric acid (1 fmol-1 pmol), which produced no change in baseline tail-flick latency, blocked all N-methyl-D-aspartate produced effects in a dose-dependent manner (100 fmol D-2-amino-5-phosphonovaleric acid produced maximum blockage for about 40 min). The magnitude and duration of N-methyl-D-aspartate-produced biphasic effects on tail-flick latency were similar in awake and lightly pentobarbital-anesthetized rats, but caudally directed biting and scratching behavior was not produced in lightly anesthetized rats. Reversible spinalization at T8-T10 in lightly anesthetized rats (produced by cold-block) completely abolished inhibition of the tail-flick reflex produced by 1 nmol N-methyl-D-aspartate whereas facilitation produced by 10 pmol N-methyl-D-aspartate remained unchanged, indicating that N-methyl-D-aspartate-produced facilitation is a local, segmental effect and that N-methyl-D-aspartate-produced inhibition requires a supraspinal loop. To examine the nature of the supraspinal loop, potential contributions of descending noradrenergic and serotonergic systems were studied. Intrathecal pretreatment with 100 nmol phentolamine completely blocked N-methyl-D-aspartate-produced inhibition of the tail-flick reflex, while N-methyl-D-aspartate-produced facilitation and caudally directed biting and scratching behavior remained unchanged. Intrathecal pretreatment with 50 nmol methysergide reversed the inhibitory effect of 1 nmol N-methyl-D-aspartate, resulting in a potent and prolonged facilitation which could be blocked by D-2-amino-5-phosphonovaleric acid. (1 pmol). Intrathecal pretreatment with an alternate substrate for nitric oxide synthase, NG-nitro-L-arginine methyl ester (100 nmol), completely blocked N-methyl-D-aspartate-produced facilitation of the tail-flick reflex, whereas N-methyl-D-aspartate-produced inhibition and caudally directed biting and scratching behavior were unaffected.(ABSTRACT TRUNCATED AT 400 WORDS)
Kolhekar
R
R
Department of Pharmacology, University of Iowa, Iowa City 52242.
Meller
S T
ST
Gebhart
G F
GF
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D003080:Cold Temperature; D006358:Hot Temperature; D008297:Male; D008784:Methysergide / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology; D019335:Nitroarginine; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology*; D010146:Pain / Q000503:physiopathology*; D010646:Phentolamine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*; D012018:Reflex / Q000187:drug effects / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects / Q000503:physiopathology*
D016194:Receptors, N-Methyl-D-Aspartate; D019335:Nitroarginine; D016202:N-Methylaspartate; D015763:2-Amino-5-phosphonovalerate; D001120:Arginine; D008784:Methysergide; D010646:Phentolamine