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

Introduction: 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). Methods: 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, alpha-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. Results: 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. Conclusion: 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.