Abstract
Metabotropic glutamate receptors (mGluRs) are involved in the modulation of synaptic transmission and plasticity. Group II mGluRs in the spinal cord regulate glutamatergic input, but their functional changes in neuropathic pain are not clear. In this study, we determined the plasticity of spinal group II mGluRs in controlling excitatory and inhibitory synaptic transmission and nociception in neuropathic pain. Neuropathic pain was induced by spinal nerve ligation in rats, and whole-cell voltage-clamp recordings of glutamatergic excitatory postsynaptic currents (EPSCs) and spontaneous and miniature GABAergic and glycinergic inhibitory postsynaptic currents (sIPSCs and mIPSCs, respectively) were performed in spinal cord slices. The specific group II mGluR agonist (2S,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)glycine (DCG-IV) had a similar inhibitory effect on monosynaptic EPSCs evoked from the dorsal root in sham and nerve-injured rats. However, DCG-IV produced a greater inhibitory effect on evoked polysynaptic EPSCs and the frequency of spontaneous EPSCs in nerve-injured rats than in control rats. Although DCG-IV similarly reduced the frequency of GABAergic sIPSCs and mIPSCs in both groups, it distinctly inhibited the frequency of glycinergic sIPSCs and mIPSCs only in nerve-injured rats. The DCG-IV effect was blocked by the group II mGluR antagonist but not by the N-methyl-d-aspartate receptor antagonist. Strikingly, intrathecal injection of DCG-IV dose-dependently attenuated allodynia and hyperalgesia in nerve-injured rats but produced hyperalgesia in control rats. Our study provides new information that nerve injury up-regulates group II mGluRs present on glutamatergic and glycinergic interneurons in the spinal cord. Activation of group II mGluRs reduces neuropathic pain probably by attenuating glutamatergic and glycinergic input to spinal dorsal horn neurons.
Footnotes
This study was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant GM64830], the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant NS45602], and the N.G. and Helen T. Hawkins Endowment (to H.L.P.).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:11.1124/jpet.110.173112.
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ABBREVIATIONS:
- mGluR
- metabotropic glutamate receptor
- EPSC
- excitatory postsynaptic current
- eEPSC
- evoked EPSC
- mEPSC
- miniature EPSC
- IPSC
- inhibitory postsynaptic current
- sIPSC
- spontaneous IPSC
- mIPSC
- miniature IPSC
- DCG-IV
- (2S,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)glycine
- EGLU
- (2S)-α-ethylglutamic acid
- GDP-β-S
- guanosine 5′-O-(2-thiodiphosphate)
- CNQX
- 6-cyano-7-nitroquinoxaline-2,3-dione
- AP-5
- 2-amino-5-phosphonopentanoic acid
- NMDA
- N-methyl-d-aspartate
- LY379268
- (1S,2R,5R,6R)-2-amino-4-oxabicyclo[3.1.0]hexane-2,6-dicarboxylic acid
- QX314
- lidocaine N-ethyl bromide
- aCSF
- artificial cerebrospinal fluid.
- Received July 19, 2010.
- Accepted October 4, 2010.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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