N-methyl- d-aspartate receptor-mediated changes in thermal nociception: Allosteric modulation at glycine and polyamine recognition sites

Abstract

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 μmol) but not l-serine or glycine to the lumbar spinal cord produced a facilitation of the tail-flick reflex at doses ⩾ 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, N G-nitro- l-arginine-methyl ester (100 nmol). Intrathecal administration of spermine (0.01 nmol−3 μmol) 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), N G-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 μmol 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.