Group II mGluRs modulate baseline and arthritis pain-related synaptic transmission in the rat medial prefrontal cortex

Abstract

The medial prefrontal cortex (mPFC) serves executive functions that are impaired in neuropsychiatric disorders and pain where abnormal synaptic inhibition of mPFC pyramidal cells has been linked to cognitive deficits. Therefore, restoring normal transmission is a desirable goal. Group II metabotropic glutamate receptors mGluR 2 and 3 are highly expressed in the mPFC, modulate excitatory and inhibitory transmission, and have been targeted for the treatment of neuropsychiatric disorders, but their pain-related modulatory effects in the mPFC remain to be determined. Here we evaluated the ability of an mGluR2/3 agonist and antagonist to restore pyramidal output in an arthritis pain model. Whole-cell patch-clamp recordings were made from visually identified layer V mPFC pyramidal cells in rat brain slices. A selective group II mGluR agonist (LY379268) decreased synaptically evoked spiking in slices from normal and arthritic rats (5-6 h postinjection of kaolin/carrageenan into one knee). 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 arthritis 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 by itself increased synaptically evoked spiking under normal conditions and in the pain model. We conclude that group II mGluRs act on glutamatergic synapses to inhibit direct excitatory transmission and feedforward inhibition onto pyramidal cells. Their net effect is deceased pyramidal cell output. The facilitatory effect of a group II antagonist suggests that the system may be tonically active to control pyramidal output and does not change in the pain model. Failure to release the inhibitory tone in conditions that require enhanced cortical function and output, such as pain control, could be a mechanism for the development or persistence of a disease state.

The Emotional Brain as a Predictor and Amplifier of Chronic Pain

“…chronic pain or transition to chronic pain activates the amygdala in relation to subjective perception of the chronic pain (Baliki et al 2006;Hashmi et al 2013). The mPFC's neuronal activity and morphology change in various animal models of persistent pain (Metz et al 2009;Kiritoshi and Neugebauer 2015). In humans, the region reflects subjective chronic pain intensity, and its functional connectivity with the NAc is predictive of transition to chronic pain (Baliki et al 2006;Baliki et al 2012;Hashmi et al 2013).…”

The Role of Stress Regulation on Neural Plasticity in Pain Chronification

“…The long-lasting sympathic pain increased neuronal excitability and dendritic branching of amygdala in rodents [90, 91], resulting in an enlarged amygdala volume [92]. Spared nerve injury sympathic pain induced alterations of dendritic length, spine density, and neuronal activity in the mPFC [93, 94], and long-term neuropathic pain reduced prefrontal volumes in rodents [95]. Moreover, hippocampal neurogenesis appeared to be suppressed in a rat model of neuropathic pain, subserving a possible mechanism of pain chronification [83, 96].…”

Group II Metabotropic Glutamate Receptors: Role in Pain Mechanisms and Pain Modulation

“…This would be consistent with endogenous activation and gain of function of mGluR2/3 in the amygdala in a pain condition. Patch-clamp recordings of CeLC neurons in rat brain slices showed that a group II mGluR agonist (LY354740) inhibited excitatory synaptic inputs (EPSCs) from the parabrachial area, which provide nociceptive information to the amygdala ( Neugebauer et al, 2004 ; Thompson and Neugebauer, 2017 ), under normal conditions, but became more potent in the arthritis pain condition ( Han et al, 2006 ; Kiritoshi and Neugebauer, 2015 ). LY354740 decrease frequency, but not amplitude, of miniature EPSCs in the presence of TTX, suggesting a presynaptic site of action on the glutamatergic terminals ( Han et al, 2006 ; Kiritoshi and Neugebauer, 2015 ).…”

“…Patch-clamp recordings of CeLC neurons in rat brain slices showed that a group II mGluR agonist (LY354740) inhibited excitatory synaptic inputs (EPSCs) from the parabrachial area, which provide nociceptive information to the amygdala ( Neugebauer et al, 2004 ; Thompson and Neugebauer, 2017 ), under normal conditions, but became more potent in the arthritis pain condition ( Han et al, 2006 ; Kiritoshi and Neugebauer, 2015 ). LY354740 decrease frequency, but not amplitude, of miniature EPSCs in the presence of TTX, suggesting a presynaptic site of action on the glutamatergic terminals ( Han et al, 2006 ; Kiritoshi and Neugebauer, 2015 ). EGLU blocked the agonist effect, but had no effect on its own, which is similar to the lack of significant effects of another group II mGluR antagonist (LY341495) at the presumed parabrachial (PB)-CeLC synapse in mouse brain slices ( Adedoyin et al, 2010 ), suggesting that the endogenous activation observed in the in vivo condition (see above) may be lost in the reduced brain slice preparation ( Han et al, 2006 ; Kiritoshi and Neugebauer, 2015 ).…”