Silva E, Cleland C L, Gebhart G F
Department of Pharmacology, University of Iowa, Iowa City 52242, USA.
Exp Brain Res. 1997 Dec;117(3):379-88. doi: 10.1007/s002210050232.
N-methyl-d-aspartate (NMDA) receptors, which are widely distributed throughout the central nervous system, appear to play a critical role in several types of plasticity and long-term potentiation. In the pain system, increased sensitivity to somatosensory stimuli, known as hyperalgesia and allodynia, can arise from tissue damage or excessive C-fiber nociceptor activation. Previously, NMDA, non-NMDA ionotropic, and metabotropic glutamate receptors have been proposed to contribute to the sustained hyperalgesia following tissue injury or nociceptor activation. Although non-NMDA receptors appear to mediate both hyperalgesia and normal (nonhyperalgesic) responses and behavior, NMDA receptors have been reported to participate only in hyperalgesic responses. In contrast, other studies have implicated NMDA receptors in both hyperalgesic and normal responses. The aim of this study was to critically compare the effects of the glutamate receptor antagonists ketamine and 2-amino-5-phosphonovaleric acid (APV; NMDA receptor antagonists), 6,7-dinitroquinoxaline-2,3-dione (DNQX; non-NMDA ionotropic receptor antagonist), and 2-amino-3-phosphonopropionic acid (AP3; metabotropic receptor antagonist) on intra-articular mustard oil-induced facilitation of flexion withdrawal reflexes in spinalized rats. Our results showed that, as expected from previous studies, ketamine, APV, and DNQX dose-dependently inhibited the flexion withdrawal reflex evoked by C-fiber electrical stimulation of the sciatic nerve. Surprisingly, however, ketamine, APV, and DNQX also inhibited flexion withdrawal reflexes in normal (nonhyperalgesic) rats with similar ED50s. In contrast, AP3 had no effect in either hyperalgesic or normal rats. These results demonstrate that NMDA and non-NMDA ionotropic, but not metabotropic, glutamate receptors contribute without preference to both facilitated and normal flexion withdrawal reflexes evoked by high-intensity electrical stimulation in the spinalized rat. Thus, the apparent preference of NMDA receptors for hyperalgesic states seen in some previous studies on nociception, as well as in other model systems, may have arisen from differences in experimental paradigm, such as the intensity of sensory stimulation or excitability of the spinal cord, coupled with the voltage dependency of the NMDA conductance.
N-甲基-D-天冬氨酸（NMDA）受体广泛分布于中枢神经系统，似乎在多种类型的可塑性和长时程增强中发挥关键作用。在疼痛系统中，对躯体感觉刺激的敏感性增加，即痛觉过敏和异常性疼痛，可能源于组织损伤或C纤维伤害感受器的过度激活。此前，有人提出NMDA、非NMDA离子型和代谢型谷氨酸受体参与了组织损伤或伤害感受器激活后的持续性痛觉过敏。虽然非NMDA受体似乎介导了痛觉过敏和正常（非痛觉过敏）反应及行为，但据报道NMDA受体仅参与痛觉过敏反应。然而，其他研究表明NMDA受体与痛觉过敏和正常反应均有关。本研究的目的是严格比较谷氨酸受体拮抗剂氯胺酮和2-氨基-5-磷酸缬氨酸（APV；NMDA受体拮抗剂）、6,7-二硝基喹喔啉-2,3-二酮（DNQX；非NMDA离子型受体拮抗剂）以及2-氨基-3-磷酸丙酸（AP3；代谢型受体拮抗剂）对关节内注射芥子油诱导的脊髓大鼠屈肌反射增强的影响。我们的结果表明，正如先前研究所预期的那样，氯胺酮、APV和DNQX剂量依赖性地抑制了坐骨神经C纤维电刺激诱发的屈肌反射。然而，令人惊讶的是，氯胺酮、APV和DNQX也以相似的半数有效剂量（ED50）抑制正常（非痛觉过敏）大鼠的屈肌反射。相比之下，AP3对痛觉过敏或正常大鼠均无影响。这些结果表明，NMDA和非NMDA离子型谷氨酸受体而非代谢型谷氨酸受体，无偏好地参与了脊髓大鼠高强度电刺激诱发的屈肌反射增强和正常反射。因此，在先前一些关于伤害感受以及其他模型系统的研究中所观察到的NMDA受体对痛觉过敏状态的明显偏好，可能源于实验范式的差异，如感觉刺激的强度或脊髓的兴奋性，以及NMDA电导的电压依赖性。
