Characterization of the role of spinal N-methyl-D-aspartate receptors in thermal nociception in the rat.

Abstract 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 T 8 –T 10 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, N G -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. In summary, these data suggest that N -methyl- d -aspartate-produced facilitation of the tail-flick reflex is a local, segmental phenomenon, but inhibition of the tail-flick reflex and caudally directed scratching and biting behavior are produced by activation of ascending pathways which, in case of the tail-flick reflex, engages descending inhibitory pathways to produce inhibition of the tail-flick reflex. Taken together, these data suggest a multiplicity of effects of N -methyl- d -aspartate receptor activation in spinal nociceptive processing.