Assessing the Effects of Opioids on Pathological Memory by a Computational Model

Opioids hijack learning and memory formation mechanisms of brain and induce a pathological memory in the hippocampus. This effect is mainly mediated by modifications in glutamatergic system. Speaking more precisely, Opioids presence in a synapse inhibits blockage of N-Methyl-D-Aspartate Receptor (NMDAR) by Mg²⁺, enhances conductance of NMDAR and thus, induces false Long-Term Potentiation (LTP).

Based on experimental observations of different researchers, we developed a mathematical model for a pyramidal neuron of the hippocampus to study this false LTP. The model contains a spine of the pyramidal neuron with NMDAR, α-Amino-3-hydroxy-5-Methyl-4-isoxazole Propionic Acid Receptors (AMPARs), and Voltage-Gated Calcium Channels (VGCCs). The model also describes Calmodulin-dependent protein Kinase II (CaMKII) and AMPAR phosphorylation processes which are assumed to be the indicators of LTP induction in the synapse.

Simulation results indicate that the effect of inhibition of blockage of NMDARs by Mg²⁺ on the false LTP is not as crucial as the effect of NMDAR's conductance modification by opioids. We also observed that activation of VGCCs has a dominant role in inducing pathological LTP.

Our results confirm that preventing this pathological LTP is possible by three different mechanisms: 1. By decreasing NMDAR's conductance; and 2. By attenuating VGCC's mediated current; and 3. By enhancing glutamate clearance rate from the synapse.