Group II mGluRs modulate baseline and arthritis pain-related synaptic transmission in the rat medial prefrontal cortex.
The medial prefrontal cortex (mPFC) serves executive control functions that are impaired in neuropsychiatric disorders and pain. Therefore, restoring normal synaptic transmission and output is a desirable goal. Group II metabotropic glutamate receptors mGluR2 and mGluR3 are highly expressed in the mPFC, modulate synaptic transmission, and have been targeted for neuropsychiatric disorders. Their pain-related modulatory effects in the mPFC remain to be determined. Here we evaluated their ability to restore pyramidal output in an arthritis pain model. Whole-cell patch-clamp recordings of layer V mPFC pyramidal cells show that a selective group II mGluR agonist (LY379268) decreased synaptically evoked spiking in brain slices from normal and arthritic rats. Effects were concentration-dependent and reversed by a selective antagonist (LY341495). LY379268 decreased monosynaptic excitatory postsynaptic currents (EPSCs) and glutamate-driven inhibitory postsynaptic currents (IPSCs) in the pain model. Effects on EPSCs preceded those on IPSCs and could explain the overall inhibitory effect on pyramidal output. LY379268 decreased frequency, but not amplitude, of miniature EPSCs without affecting miniature IPSCs. LY341495 alone increased synaptically evoked spiking under normal conditions and in the pain model. In conclusion, group II mGluRs act on glutamatergic synapses to inhibit direct excitatory transmission and feedforward inhibition onto pyramidal cells. Their net effect is decreased pyramidal cell output. Facilitatory effects of a group II antagonist suggest the system may be tonically active to control pyramidal output. Failure to release the inhibitory tone and enhance mPFC output could be a mechanism for the development or persistence of a disease state such as pain.
Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center (TTUHSC), School of Medicine, 3601 4th Street, Mail Stop 6592, Lubbock, TX 79430-6592, USA.
Takaki
T
Kiritoshi
Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center (TTUHSC), School of Medicine, 3601 4th Street, Mail Stop 6592, Lubbock, TX 79430-6592, USA; Center of Excellence for Translational Neuroscience and Therapeutics, Texas Tech University Health Sciences Center (TTUHSC), School of Medicine, 3601 4th Street, Mail Stop 6592, Lubbock, TX 79430-6592, USA. Electronic address: volker.neugebauer@ttuhsc.edu.
Volker
V
Neugebauer
D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D001169:Arthritis, Experimental / Q000503:physiopathology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D007616:Kaolin; D055369:Miniature Postsynaptic Potentials / Q000187:drug effects; D010146:Pain / Q000188:drug therapy* / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000503:physiopathology; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D046509:Tissue Culture Techniques; D014966:Xanthenes / Q000494:pharmacology
D000596:Amino Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C114624:LY 341495; C118218:LY 379268; D018094:Receptors, Metabotropic Glutamate; D014966:Xanthenes; D007616:Kaolin
Medial prefrontal cortex; Pain; Patch-clamp; Synaptic transmission; mGluR