RESUMO
Neuropathic pain is caused by nerve injury and involves brain areas such as the central nucleus of the amygdala (CeA). We developed the first 3-D agent-based model (ABM) of neuropathic pain-related neurons in the CeA using NetLogo3D. The execution time of a single ABM simulation using realistic parameters (e.g., 13,000 neurons and 22,000+ neural connections) is an important factor in the model's usability. In this paper, we describe our efforts to improve the computational efficiency of our 3-D ABM, which resulted in a 28% reduction in execution time on average for a typical simulation. With this upgraded model, we performed one- and two-parameter sensitivity analyses to study the sensitivity of model output to variability in several key parameters along the anterior to posterior axis of the CeA. These results highlight the importance of computational modeling in exploring spatial and cell-type specific properties of brain regions to inform future wet lab experiments.
RESUMO
Chronic bladder pain evokes asymmetric behavior in neurons across the left and right hemispheres of the amygdala. An agent-based computational model was created to simulate the firing of neurons over time and in response to painful bladder stimulation. Each agent represents one neuron and is characterized by its location in the amygdala and response type (excited or inhibited). At each time step, the firing rates (Hz) of all neurons are stochastically updated from probability distributions estimated from data collected in laboratory experiments. A damage accumulation model tracks the damage accrued by neurons during long-term, painful bladder stimulation. Emergent model output uses neural activity to measure temporal changes in pain attributed to bladder stimulation. Simulations demonstrate the model's ability to capture acute and chronic pain and its potential to predict changes in pain similar to those observed in the lab. Asymmetric neural activity during the progression of chronic pain is examined using model output and a sensitivity analysis.
RESUMO
Abstract: Morphine is a well-characterized and effective analgesic commonly used to provide pain relief to patients suffering from both acute and chronic pain conditions. Despite its widespread use and effectiveness, one of the major drawbacks of morphine is its relatively short half-life of approximately 4 h. This short half-life often necessitates multiple administrations of the drug each day, which may contribute to both dependence and tolerance to morphine. Here, we tested the analgesic properties of a new polymer form of morphine known as PolyMorphine. This polymer has monomeric units of morphine incorporated into a poly(anhydride-ester) backbone that has been shown to hydrolyze into free morphine in vitro. Using an animal model of chronic pain, the spared nerve injury surgery, we showed that PolyMorphine is able to block spared nerve injury-induced hypersensitivity in mice for up to 24-h post-administration. Free morphine was shown to only block spared nerve injury-induced hypersensitivity for up to 2-h post-injection. PolyMorphine was also shown to act through the mu opioid receptor due to the ability of naloxone (a mu opioid receptor antagonist) to block PolyMorphine-induced analgesia in spared nerve injury animals pretreated with PolyMorphine. Additionally, we observed that PolyMorphine causes similar locomotor and constipation side effects as free morphine. Finally, we investigated if PolyMorphine had any effects in a non-evoked pain assay, conditioned place preference. Pretreatment of spared nerve injury mice with PolyMorphine blocked the development of conditioned place preference for 2-methyl-6-(phenylethynyl)pyridine (MPEP), a short-lasting mGluR5 antagonist with analgesic-like properties. Free morphine does not block the development of preference for MPEP, suggesting that PolyMorphine has longer lasting analgesic effects compared to free morphine. Together, these data show that PolyMorphine has the potential to provide analgesia for significantly longer than free morphine while likely working through the same receptor.