Kolhekar R, Meller S T, Gebhart G F
Department of Pharmacology, University of Iowa, Iowa City 52242.
Neuroscience. 1994 Dec;63(4):925-36. doi: 10.1016/0306-4522(94)90560-6.
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.
在清醒大鼠中研究了N-甲基-D-天冬氨酸受体离子通道复合物的变构调节剂对伤害性甩尾反射的影响。向腰段脊髓鞘内注射D-丝氨酸（100飞摩尔至1微摩尔）而非L-丝氨酸或甘氨酸，在剂量≥1皮摩尔时（0.5 - 1分钟时达到最大值）可促进甩尾反射。鞘内预先注射甘氨酸调节位点拮抗剂7-氯犬尿氨酸（3皮摩尔）可阻断D-丝氨酸和N-甲基-D-天冬氨酸引起的甩尾反射促进作用。鞘内预先注射N-甲基-D-天冬氨酸受体离子通道阻滞剂MK 801（100飞摩尔）或一氧化氮合酶的替代底物NG-硝基-L-精氨酸甲酯（100纳摩尔）也可阻断D-丝氨酸引起的促进作用。鞘内注射精胺（0.01纳摩尔至3微摩尔）对甩尾潜伏期产生双相效应，更高剂量时伴有机械性感觉过敏和发声。精胺引起的促进作用（1分钟时0.01纳摩尔至1纳摩尔时达到最大值）可被鞘内预先注射MK 801（100飞摩尔）、NG-硝基-L-精氨酸甲酯（100纳摩尔）或多胺调节位点拮抗剂阿卡因（10纳摩尔）阻断。精胺引起的抑制作用（2分钟时300纳摩尔时达到最大值）可被鞘内注射MK 801（1纳摩尔）阻断。鞘内注射N-甲基-D-天冬氨酸受体拮抗剂D-2-氨基-5-磷酸戊酸（1纳摩尔）可阻断抑制作用，并揭示1微摩尔精胺产生的促进作用。此外，精胺产生多阶段运动效应（即时和延迟发作）。鞘内预先注射MK 801（1纳摩尔）仅阻断即时发作的运动效应，而延迟发作的运动效应可被κ阿片受体拮抗剂去甲二氢吗啡酮（200纳摩尔）预先处理选择性阻断。综上所述，这些数据表明D-丝氨酸和精胺通过对N-甲基-D-天冬氨酸受体离子通道的正变构调节促进伤害性信号传递。此外，N-甲基-D-天冬氨酸受体的激活对于引发即时发作的运动效应以及更高剂量精胺产生的甩尾反射抑制也是必需的。由于κ阿片受体似乎参与其中，精胺产生的延迟发作运动效应可能涉及内源性强啡肽释放。
