Inhibitory effects of Group I metabotropic glutamate receptors antagonists on the expression of NMDA receptor NR1 subunit in morphine tolerant rats

N-Methyl-d-aspartate receptor (NMDAR) and Group I metabotropic glutamate receptors (mGluRs) are involved in the process of morphine tolerance. Previous studies have shown that Group I mGluRs can modulate NMDAR functions in the central nervous system. The aim of the present study was to examine the influence of Group I mGluRs antagonists on the expression of NMDA receptor NR1 subunit (NR1) in the rat spinal cord. Morphine tolerance was induced in rats by repeated administration of 10 μg morphine (intrathecal, i.t.) twice a day for 7 consecutive days. Tail flick test was used to assess the effect of Group I mGluRs antagonist, AIDA ((RS)-1-Aminoindan-1,5 dicarboxylic acid) or mGluR5 antagonist, MPEP (2-methyl-6-(phenylethynyl)pyridine) on morphine antinociceptive tolerance. The expression of NR1 was measured by immunofluorescence and Western blot. Behavioral tests revealed that both AIDA and MPEP attenuated the development of morphine tolerance. The expression of NR1 was upregulated in the dorsal horn of spinal cord after chronic morphine treatment. AIDA or MPEP co-administered with morphine attenuated morphine induced upregulation of NR1. These findings suggest that the development of morphine tolerance partly prevented by Group I mGluRs antagonists may due to its inhibitory effect on the expression of NR1 subunit.     

Effects of activation of group III metabotropic glutamate receptors on spinal synaptic transmission in a rat model of neuropathic pain

Chronic neuropathic pain remains an unmet clinical problem because it is often resistant to conventional analgesics. Metabotropic glutamate receptors (mGluRs) are involved in nociceptive processing at the spinal level, but their functions in neuropathic pain are not fully known. In this study, we investigated the role of group III mGluRs in the control of spinal excitatory and inhibitory synaptic transmission in a rat model of neuropathic pain induced by L5/L6 spinal nerve ligation. Whole-cell recording of lamina II neurons was performed in spinal cord slices from control and nerve-ligated rats. The baseline amplitude of glutamatergic EPSCs evoked from primary afferents was significantly larger in nerve-injured rats than in control rats. However, the baseline frequency of GABAergic and glycinergic inhibitory postsynaptic currents (IPSCs) was much lower in nerve-injured rats than in control rats. The group III mGluR agonist l(+)-2-amino-4-phosphonbutyric acid (l-AP4) produced a greater inhibition of the amplitude of monosynaptic and polysynaptic evoked EPSCs in nerve-injured rats than in control rats. l-AP4 inhibited the frequency of miniature EPSCs in 66.7% of neurons in control rats but its inhibitory effect was observed in all neurons tested in nerve-injured rats. Furthermore, l-AP4 similarly inhibited the frequency of GABAergic and glycinergic IPSCs in control and nerve-injured rats. Our study suggests that spinal nerve injury augments glutamatergic input from primary afferents but decreases GABAergic and glycinergic input to spinal dorsal horn neurons. Activation of group III mGluRs attenuates glutamatergic input from primary afferents in nerve-injured rats, which could explain the antinociceptive effect of group III mGluR agonists on neuropathic pain.     

Variation of CS salience reveals group II mGluR-dependent and -independent forms of conditioning in the rat

There is good evidence that metabotropic glutamate receptors (mGluRs) are involved in some types of learning, and we have previously suggested that this involvement may reflect the modulation by mGluRs of the signal-to-noise ratio in neural networks. This hypothesis supposes that unspecific activation of mGluRs increases background noise level, so reducing the effectiveness of behaviourally relevant stimuli as signals in the network. We report here that intraperitoneal (i.p.) injection of 4-aminopyrrolidine-2,4-dicarboxylic acid (APDC), a specific agonist of group II mGluRs, disrupts conditioning to context (but not to cue) using conventional procedures. The hypothesis predicts, however, that the effect of the drug should be counteracted by the use of more salient stimuli, which would provide stronger signals to the network. In accordance with this prediction, we find that increases in the salience of either the CS (context) or the UCS (shock) abolish the drug-induced disruption of conditioning. These results suggest that group II mGluRs modulate neural networks involved in association formation.     

运动疲劳对大鼠皮质M1区mGluR1和mGluR5蛋白表达的影响

目的:疲劳是导致机体工作能力下降的重要原因,通过观察反复力竭运动大鼠皮质主运动区中mGluR1和mGluR5在运动前后的表达变化,探讨Ⅰ组代谢型谷氨酸受体介导运动疲劳产生的作用效应。方法:选用雄性Wistar大鼠32只,随机分为对照组(CG)、力竭即刻组(0EG)和运动后24h组(24EG),运动后48h组(48EG),每组8只,采用免疫组化染色和计算机图像分析系统检测并观察各组mGluR1和mGluR5表达的阳性细胞数和积分光密度(IOD)。结果:与对照组相比,力竭后即刻组及运动后24h组,大鼠皮质主运动区中mGluR1和mGluR5阳性细胞数量和IOD值均显著升高(P<0.05);运动后48h组mGluR1的蛋白表达较对照组仍有显著升高(P<0.05),而运动后48h组的mGluR5蛋白表达和对照组无显著差异(P>0.05)。结论:运动疲劳可导致大鼠中枢运动皮质代谢型谷氨酸受体的表达上调,不同亚型受体蛋白表达的时间效应不一样,提示mGluR1和mGluR5可能是中枢神经系统中介导运动疲劳产生的重要新型受体靶点。