How does the endogenous opioid system modulate excitatory and inhibitory synapses in the anterior cingulate cortex?

     ​ Sustained pain-induced activation of the anterior cingulate cortex promotes the release of endogenous opioids and behaviors associated with pain relief, however, the underlying mechanisms of these processes are not completely understood yet. Tanaka & North (1994) reported that met-enkephalin, an endogenous opioid peptide with high affinity for mu and delta opioids receptors inhibits synaptic potentials recorded from layer V pyramidal neurons elicited by subthreshold electrical stimulation of the white matter. They also found that DPDPE, a delta-opioid receptor agonist, mimics the effect of met-enkephalin on the membrane potential but the mu-opioid receptor agonist DAMGO does not. Later, Birdsong et al. (2016) showed that optically driven thalamic-mediated excitatory synaptic currents are sensitive to DAMGO but not DPDPE, whereas inhibitory synaptic currents are sensitive to both DAMGO and DPDPE. These apparently conflicting results posit a challenge to our current understanding of the mechanisms by which endogenous opioid systems coordinate the functional state of this cortical network important for pain perception and modulation. Therefore, the goal of my current project is to define a discrete mechanism by which endogenous opioids, such as met-enkephalin, control excitation-inhibition balance in ACC pyramidal neurons.

Experimental paradigm. A. Male or female ~4-week old mice are injected in the mediodorsal thalamus (MD) with AAV2-ChR2-H134R-YFP and cholera toxin fused to a red fluorescent protein. The injected mice are sacrificed between days 14 - 17 post-surgery and electrophysiology experiments are performed. B. Nerve fibers of thalamic origin expressing channelrhodopsin (ChR2) and projecting to the ACC and the striatum are shown in green, fibers from the ACC projecting to the MD retrogradely labeled with cholera toxin are shown in red. C. Schematic representation of the local circuits in the ACC. Inputs to the ACC come from the mediodorsal, the anteromedial, and the ventromedial thalamus; the insular, the cingular, and the prefrontal cortices, and subcortical structures such as the amygdala, the substantia nigra, and the claustrum. In our model, synaptic inputs from the mediodorsal thalamus expressing ChR2 can be selectively activated with 670 nm wavelength light pulses to evoke inhibitory or excitatory synaptic responses from layer V pyramidal cells that can be recorded with patch electrodes. D. Sample traces of inhibitory and excitatory synaptic currents isolated electrically in the baseline condition, in presence of a saturating concentration of met-enkephalin, and after drug washout, respectively (credits: Paxinos and Franklin's "The Mouse Brain in Stereotaxic Coordinates", 5th ed., micrograph on B and sample traces shown on D are courtesy of Dr. William Birdsong.)

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