Contributions of glutamate receptors to the maintenance of mustard oil-induced hyperalgesia in spinalized rats.

Abstract

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.