Fig 1.
Neurobiology of opioid signaling studied in this work.
The model consists of a pyramidal neuron’s bouton and a GABAergic single compartment interneuron from CA3 layer, and a spine of a postsynaptic CA1 pyramidal neuron and an astrocyte. The astrocyte monitors the synaptic transmission, regulates presynaptic glutamate release and is involved in the postsynaptic transmission by releasing gliotransmitters.
Fig 2.
Block diagram of different parts of the proposed model.
External stimulation is followed by action potential generation in the presynaptic pyramidal neuron and the interneuron. Consequently, level of presynaptic calcium is elevated through two fast and slow mechanisms. Fast calcium oscillations are due to APs, and slow ones are because of IP3 production. Gliotransmitters activate mGlurs and contribute to slow calcium oscillations by IP3 production. Calcium enhancement results in glutamate release. Interneuron’s activation modulates GABA receptors in pyramidal neuron and is sensitive to the opioid receptor’s activation. Released glutamate reaches to the postsynaptic neuron and the astrocyte. The astrocyte releases gliotransmitter which affects presynaptic and postsynaptic neurons. Functions of AMPARs and NMDARs are considered in the postsynaptic neuron. Activation of the receptors enables CaMKII phosphorylation process. Exceeding phosphorylated CaMKII from a threshold leads to NO production which retrogrades to the presynaptic neuron. Finally, postsynaptic opioid receptors modulate NMDARs activation.
Fig 3.
Shows the percentage of activated μORs versus different dose of morphine.
Fig 4.
The activation of the interneuron calcium channel and the amplitude of the IPSC in the pyramidal neuron are shown for three different doses of morphine (μM).
(A) morphine concentration considered to be 0, (B) shows the results for 0.1 μM concentration of morphine and (C) is the simulation results at 1 μM concentration of morphine.
Fig 5.
Activated VGCCs versus different doses of morphine (μM) in experimental conditions (red line) and simulation setup (black line) are described here.
Fig 6.
Inhibition of IPSC in response to different doses of morphine (μM) in experimental study (black line) and simulation condition (red line) are shown here.
Fig 7.
Simulation results for normal condition has been denoted here.
Synaptic glutamate is shown in (A), gliotransmitter dynamics is denoted in (B), presynaptic IP3 variation and Ca2+ oscillations are shown in (C) and (D), respectively; AMPAR and NMDAR currents are denoted in (E) and (F), postsynaptic Ca2+ is shown in (G), phosphorylated CaMKII and NOs threshold are shown in (H) by red and green curves, respectively.
Fig 8.
Results of the simulations in pathological conditions with an injection of 1 μM morphine have been denoted.
Synaptic glutamate is shown in (A), gliotransmitter dynamics is denoted in (B), presynaptic IP3 variation and Ca2+ oscillations are shown in (C) and (D), respectively, postsynaptic Ca2+ is shown in (E), and finally, phosphorylated CaMKII and the threshold for NOs are shown in (F) with red and green lines, respectively.
Fig 9.
A comparison between the normal (A) and the pathological (B) conditions is shown.
Fig 10.
Box and whisker plot for different simulations have been described here.
Redline shows the median of the signals, ‘+’ sign represents the mean value of each signal, blue line demonstrates that 25%-75% of data are included in this range, and finally black line shows the range that 9%-91% of the dada are included. Panel A shows the synaptic glutamate, Panel B denotes the gliotransmitter, Panel C describes the phosphorylated CaMKII, and Panel D represents the Phosphorylated AMPARs. In the first simulation, all of the synaptic components are affected by morphine and the simulation of 13th indicates normal mode. In the second simulation, the effect of morphine on presynaptic neurons has been neglected. In the third simulation, postsynaptic μORs are assumed to be inactive. In the fourth simulation, morphine only affects astrocyte. In the fifth simulation, the release of the gliotransmitter is considered zero. In the sixth simulation, it is assumed that despite the effect of morphine on all the components of the synapse, astrocytic GLTs act normal. In the seventh simulation, under conditions where morphine affects all of the synaptic components, the activity of astrocytic transporters is stimulated to be 50% greater than normal. In the eighth simulation, the activity of astrocytic mGlurs is considered zero. The ninth simulation shows that astrocytic mGlurs and postsynaptic μORs are not active. In the tenth simulation, astrocytic transporters are stimulated 50% more than normal, and astrocytic mGlurs have been deactivated. In the eleventh simulation, by stimulating astrocytic transporters, NMDA receptors have a normal synaptic effect. In the 12th simulation, astrocytic mGlurs have been deactivated, astrocytic transporters are stimulated, and NMDARs act as normal.
Fig 11.
Normalized graph of monitoring factors for different simulations has been described here.