Zhang H-M, Chen S-R, Pan H-L
Department of Anesthesiology and Pain Medicine, Unit 110, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Neuroscience. 2009 Jan 23;158(2):875-84. doi: 10.1016/j.neuroscience.2008.10.042. Epub 2008 Oct 30.
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.
慢性神经性疼痛仍然是一个尚未解决的临床问题，因为它通常对传统镇痛药具有抗性。代谢型谷氨酸受体（mGluRs）参与脊髓水平的伤害性感受处理，但其在神经性疼痛中的功能尚不完全清楚。在本研究中，我们在L5/L6脊髓神经结扎诱导的神经性疼痛大鼠模型中，研究了III组mGluRs在控制脊髓兴奋性和抑制性突触传递中的作用。在对照大鼠和神经结扎大鼠的脊髓切片中对II层神经元进行全细胞记录。与对照大鼠相比，神经损伤大鼠中由初级传入纤维诱发的谷氨酸能兴奋性突触后电流（EPSCs）的基线幅度显著更大。然而，与对照大鼠相比，神经损伤大鼠中GABA能和甘氨酸能抑制性突触后电流（IPSCs）的基线频率要低得多。与对照大鼠相比，III组mGluR激动剂L(+)-2-氨基-4-膦酰丁酸（L-AP4）对神经损伤大鼠中单突触和多突触诱发的EPSCs幅度的抑制作用更大。L-AP4在66.7%的对照大鼠神经元中抑制微小EPSCs的频率，但在神经损伤大鼠中测试的所有神经元中均观察到其抑制作用。此外，L-AP4在对照大鼠和神经损伤大鼠中同样抑制GABA能和甘氨酸能IPSCs的频率。我们的研究表明，脊髓神经损伤增强了初级传入纤维的谷氨酸能输入，但减少了脊髓背角神经元的GABA能和甘氨酸能输入。III组mGluRs的激活减弱了神经损伤大鼠中初级传入纤维的谷氨酸能输入，这可以解释III组mGluR激动剂对神经性疼痛的镇痛作用。
