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

Abstract

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 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.

Functional Plasticity of Group II Metabotropic Glutamate Receptors in Regulating Spinal Excitatory and Inhibitory Synaptic Input in Neuropathic Pain

“…Group II mGluRs are present in the dorsal root ganglion and spinal superficial dorsal horn (Jia et al, 1999;Carlton et al, 2001), and stimulation of these mGluRs in the spinal cord generally depresses synaptic transmission (Gerber et al, 2000;Zhou et al, 2007). We have demonstrated that activation of group I and group III mGluRs has distinct effects on synaptic transmission in the spinal dorsal horn in neuropathic pain Zhang et al, 2009;Li et al, 2010). In contrast, the nerve injury-induced changes in group II mGluR function in the spinal dorsal horn and their functional significance in neuropathic pain is still not clear.…”

“…Recordings of postsynaptic currents were performed by using the whole-cell voltage-clamp method, as described previously (Zhou et al, 2008a(Zhou et al, , 2009Zhang et al, 2009). Each slice was placed in a glass-bottomed chamber and continuously perfused with Krebs' solution at 5.0 ml/min at 34°C maintained by an inline solution heater and a temperature controller.…”

“…Signals were recorded with an amplifier (MultiClamp 700B; Molecular Devices, Sunnyvale, CA), filtered at 1 to 2 kHz, digitized at 10 kHz, and stored into a computer with pCLAMP 9.2 (Molecular Devices). The evoked EPSCs (eEPSCs) of lamina II neurons were induced by electrical stimulation (0.8 mA, 0.2 ms, 0.2 Hz) of the dorsal root (Zhou et al, 2008a;Zhang et al, 2009). Because the retained dorsal root was very short, we did not measure the conduction velocity of afferent fibers stimulated.…”

“…Increased glutamatergic synaptic inputs to spinal dorsal horn neurons play a pivotal role in the development and maintenance of central sensitization and neuropathic pain conditions (Kohno et al, 2003;Wang et al, 2007;Zhang et al, 2009). Glutamate is a major excitatory neurotransmitter released from primary afferents and interneurons in the spinal cord.…”

N-Methyl-d-aspartate Receptor- and Calpain-mediated Proteolytic Cleavage of K+-Cl− Cotransporter-2 Impairs Spinal Chloride Homeostasis in Neuropathic Pain

“…Glutamate-mediated synaptic input and NMDAR activity of lamina II neurons are increased in spinal cords of SNL rats (32,33). We determined whether increased NMDAR activity contributes to synaptic disinhibition and the shift in E glycine of lamina II neurons caused by nerve injury.…”