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Group II mGluRs modulate baseline and arthritis pain-related synaptic transmission in the rat medial prefrontal
Takaki Kiritoshi1, Volker Neugebauer2
1Department 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.
Abstract:
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.
Insights
Group II metabotropic glutamate receptors (mGluRs) in the medial prefrontal cortex (mPFC) inhibit pyramidal cell output, potentially contributing to pain states. Antagonists may restore normal mPFC function.
Area of Science:
- Neuroscience
- Synaptic Transmission
- Pain Research
Background:
- The medial prefrontal cortex (mPFC) is crucial for executive functions, often impaired in neuropsychiatric disorders and pain.
- Group II metabotropic glutamate receptors (mGluR2/3) are abundant in the mPFC and modulate synaptic activity, making them therapeutic targets.
Purpose of the Study:
- To investigate the role of group II mGluRs in modulating mPFC pyramidal cell output in an arthritis pain model.
- To determine if group II mGluRs can restore normal pyramidal output in pain conditions.
Main Methods:
- Whole-cell patch-clamp recordings were performed on layer V mPFC pyramidal cells in brain slices from normal and arthritic rats.
- Selective group II mGluR agonist (LY379268) and antagonist (LY341495) were used to assess effects on synaptic transmission and neuronal spiking.
Main Results:
- LY379268 decreased synaptically evoked spiking in a concentration-dependent manner, an effect reversible by LY341495.
- The agonist reduced excitatory postsynaptic currents (EPSCs) and inhibitory postsynaptic currents (IPSCs), with EPSC effects preceding IPSC modulation.
- LY379268 decreased miniature EPSC frequency but not amplitude, suggesting presynaptic inhibition.
- LY341495 alone enhanced synaptically evoked spiking in both normal and pain states.
Conclusions:
- Group II mGluRs inhibit pyramidal cell output in the mPFC by reducing excitatory transmission and feedforward inhibition.
- A tonic inhibitory tone mediated by group II mGluRs likely controls mPFC output.
- Dysregulation of this inhibitory tone may contribute to the pathophysiology of pain and other disorders.
