Kolhekar R, Gebhart G F
Department of Pharmacology, University of Iowa, Iowa City 52242.
Brain Res. 1994 Jul 18;651(1-2):215-26. doi: 10.1016/0006-8993(94)90700-5.
The effects of N-methyl-D-aspartic acid (NMDA; 100 fmol-1 nmol) or quisqualic acid (QA; 10 pmol-10 nmol) on visceromotor and pressor responses to noxious colorectal distention (CRD; 40 mmHg, 20 s duration, interstimulus interval: 4 min) were studied in awake rats. Lesser doses of NMDA (100 fmol-1 pmol) administered intrathecally (i.t.) to the lumbar spinal cord produced a dose-dependent facilitation of visceromotor as well as pressor responses to CRD (maximum with 1 pmol NMDA at 1 min). The greatest dose tested (1 nmol) attenuated these responses (maximum at 1 min) and also produced a caudally-directed biting and scratching behavior accompanied by vocalizations. NMDA did not produce any of the above effects when administered i.t. to the thoracic spinal cord. I.t. pretreatment with the NMDA receptor antagonist, D-2-amino-5-phosphonovaleric acid (D-APV; 1 pmol), which produced no change in baseline activity or control responses, blocked all NMDA-produced effects in a reversible manner. QA produced dose-dependent inhibitory effects on visceromotor as well as pressor responses to noxious CRD when given i.t. to the lumbar spinal cord but not on administration to the thoracic spinal cord. Three nmol QA produced maximum inhibition at 2 min after administration and also produced caudally-directed biting and scratching. All of the QA-produced effects were reversibly blocked by i.t. pretreatment with the non-NMDA receptor antagonist, 6,7-dinitroquinoxaline-2,3-dione (DNQX; 3 nmol), which produced no change in baseline activity or control responses. We also examined the effects of NMDA and QA on responses to graded intensities of CRD. One pmol NMDA selectively facilitated visceromotor responses to CRD at distention pressures of 40 and 80 mmHg but not at 20 mmHg. In contrast, 3 nmol QA inhibited visceromotor responses to CRD at all intensities tested. In summary, these data suggest that activation of NMDA and non-NMDA receptors in the spinal cord differentially modulates visceral nociceptive input. Spinal segmental NMDA receptor activation produces selective facilitation of visceral nociceptive processing at noxious intensities of stimulation and may thereby contribute to central mechanisms underlying visceral hyperalgesia.
在清醒大鼠中，研究了N-甲基-D-天冬氨酸（NMDA；100飞摩尔至1纳摩尔）或喹啉酸（QA；10皮摩尔至10纳摩尔）对有害结肠扩张（CRD；40毫米汞柱，持续20秒，刺激间隔：4分钟）引起的内脏运动和升压反应的影响。向腰段脊髓鞘内注射较小剂量的NMDA（100飞摩尔至1皮摩尔）可产生剂量依赖性地促进对CRD的内脏运动和升压反应（1皮摩尔NMDA在1分钟时作用最强）。所测试的最大剂量（1纳摩尔）减弱了这些反应（1分钟时最大），还产生了伴有叫声的尾向咬和抓挠行为。当向胸段脊髓鞘内注射NMDA时，未产生上述任何效应。用NMDA受体拮抗剂D-2-氨基-5-膦酰基戊酸（D-APV；1皮摩尔）进行鞘内预处理，该预处理对基础活动或对照反应无影响，但以可逆方式阻断了所有NMDA产生的效应。当向腰段脊髓鞘内注射QA时，对有害CRD引起的内脏运动和升压反应产生剂量依赖性抑制作用，但向胸段脊髓注射时则无此作用。3纳摩尔QA在给药后2分钟产生最大抑制作用，还产生尾向咬和抓挠。所有QA产生的效应均被鞘内注射非NMDA受体拮抗剂6,7-二硝基喹喔啉-2,3-二酮（DNQX；3纳摩尔）预处理以可逆方式阻断，该预处理对基础活动或对照反应无影响。我们还研究了NMDA和QA对不同强度CRD反应的影响。1皮摩尔NMDA选择性地促进在40和80毫米汞柱扩张压力下对CRD的内脏运动反应，但在20毫米汞柱时无此作用。相反，3纳摩尔QA在所有测试强度下均抑制对CRD的内脏运动反应。总之，这些数据表明脊髓中NMDA和非NMDA受体的激活对内脏伤害性传入进行不同的调节。脊髓节段性NMDA受体激活在有害刺激强度下选择性地促进内脏伤害性处理，因此可能有助于内脏痛觉过敏的中枢机制。
