Functional consequences of the interactions between tau protein and opioids
Document text
Principal Investigator: Brady Atwood Organization: UNIVERSITY OF MINNESOTA Fiscal Year: 2024 Award: $239,963 Funding agency: National Institute on Drug Abuse PROJECT SUMMARY The opioid epidemic is a persistent public health crisis that has been worsened by the COVID19 pandemic. Efforts to curtail this epidemic have had minimal success in halting its continued progression. There is a critical need to more fully understand the neurobiology of opioid use disorder so that highly novel therapeutics can be developed. Recent clinical and preclinical studies have found that opioid use increases the levels of phosphory- lated tau protein in the brain, especially in the prefrontal cortex. The prefrontal cortex plays a significant role in the control of opioid use. Hyperphosphorylated tau is a hallmark of neurodegenerative tauopathy-related dis- eases such as Alzheimer’s Disease and frontotemporal dementia. However, opioid use does not appear to be a major predisposing factor in the development of these diseases. This begs the question of whether opioid-in- duced increases in phosphorylated tau are a simple byproduct of opioid use with no significant role in brain health, or if this increase has significant biological relevance for mediating the neurobehavioral consequences of opioid use. Focusing research efforts on whether opioid use produces neurodegenerative diseases may lead to a missed opportunity to explore a non-neurodegenerative role for opioid-induced changes in tau biology. It is known that hyperphosphorylated tau can and tau oligomerization alter neurotransmission long before tau-related pathology is observable. Therefore, we reason that opioid-induced increases in phosphorylated tau and tau oli- gomerization may alter prefrontal cortical neurotransmission in the absence of any overt pathology. This project proposal tests the hypothesis that opioids produce enhanced tau phosphorylation and oligomerization in the prefrontal cortex leading to synaptic dysfunction and elevated opioid consumption. We will focus on the opioid oxycodone in this project due its long-term use to treat pain as well as its common misuse in those with opioid use disorder. We will use a multidisciplinary approach to test for a causative role for prefrontal cortical tau in producing synaptic dysfunction and enhancing oxycodone consumption. This project is high-risk, high-reward. It is conceivable that opioid-induced changes in tau have nothing to do with synaptic changes or oxycodone con- sumption. However, if there is a connection between opioid-induced changes in tau biology and synaptic changes and opioid use, then this will be a paradigm shift for the opioid research field. In the future, after some additional exploration, we may be able to leverage therapeutics originally designed to treat neurodegenerative tauopathies to treat opioid use disorder. This would be an entirely new avenue for combatting the opioid epi- demic. Terms: <4-Aminobutanoic Acid><4-Aminobutyric Acid><4-amino-butanoic acid><AAV vector><AAV-based vector><AD dementia><Access to Care><Adult females><Adult women><Affect><Age><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer risk factor><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's disease risk><Alzheimers Dementia><Aminalon><Aminalone><Analgesic Agents><Analgesic Drugs><Analgesic Preparation><Analgesics><Anodynes><Anterior><Antinociceptive Agents><Antinociceptive Drugs><Autopsy><Behavior><Behavior assessment><Behavior-Related Disorder><Behavior-Related Problem><Biochemical><Biological><Biology><Brain><Brain Nervous System><Brain region><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 years><Chronic><Clinical Pathology><Clinical Research><Clinical Study><Consumption><Curiosities><Data><Degenerative Neurologic Disorders><Development><Dihydrohydroxycodeinone><Disease><Disorder><Dose><Drugs><Dysfunction><Education><Educational aspects><Electrophysiology><Electrophysiology (science)><Encephalon><Epidemic><Females in adulthood><Formulation><Foundations><Frontal Temporal Dementia><Frontotemporal Dementia><Functional disorder><Future><GABA><Glutamates><Goals><Health><Health Services Accessibility><Hortega cell><Immunoblotting><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Individual><Injections><KO mice><Kinases><Knock-out><Knock-out Mice><Knockout><Knockout Mice><L-Glutamate><Lifestyle-Related Disorder><Lifestyle-Related Problem><Lifestyle-related condition><Link><MT-bound tau><Medial><Mediating><Mediator><Medication><Mice><Mice Mammals><Microglia><Murine><Mus><Nerve Degeneration><Nerve Impulse Transmission><Nerve Transmission><Nervous System Degenerative Diseases><Neural Degenerative Diseases><Neural Transmission><Neural degenerative Disorders><Neurobiology><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neuron Degeneration><Neuronal Transmission><Neurophysiology - biologic function><Neurophysiology / Electrophysiology><Null Mouse><Opiate Addiction><Opiate Dependence><Opiates><Opioid><Oral><Oxycodeinon><Oxycodone><Oxycodone SR><Oxycontin><Pain><Pain Control><Pain Therapy><Pain management><Painful><Pathology><Persons><Pharmaceutical Preparations><Phosphorylation><Phosphotransferase Gene><Phosphotransferases><Physiopathology><Play><Policies><Predisposing Factor><Prefrontal Cortex><Primary Senile Degenerative Dementia><Process><Protein Phosphorylation><Proteins><Public Health><Regimen><Research><Rewards><Role><Roxicodone><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><Saline><Saline Solution><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Slice><Synapses><Synaptic><Synaptic Transmission><Tauopathies><Testing><Therapeutic><Transmission><Transphosphorylases><Western Blotting><Western Immunoblotting><Wild Type Mouse><Women in adulthood><Work><abnormally aggregated tau protein><access to health services><access to services><access to treatment><accessibility to health services><addiction><addictive disorder><adeno-associated viral vector><adeno-associated virus vector><ages><alzheimer risk><availability of services><axon signaling><axon-glial signaling><axonal signaling><behavior response><behavioral assessment><behavioral response><biologic><brain health><brain tissue><care access><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><design><designing><developmental><drinking><drug/agent><electrophysiological><filamentous tau inclusion><front temporal dementia><frontal lobe dementia><frontotemporal lobar dementia><frontotemporal lobe degeneration associated with dementia><gamma-Aminobutyric Acid><gitter cell><glia signaling><glial signaling><glutamatergic><health service access><health services availability><high reward><high risk><hyper-phosphorylated tau><hyperphosphorylated tau><interdisciplinary approach><male><mesoglia><microglial cell><microgliocyte><microtubule associated protein tau aggregation><microtubule associated protein tau deposit><microtubule bound tau><microtubule-bound tau><mouse model><multidisciplinary approach><murine model><necropsy><nerve signaling><neural degeneration><neural function><neural inflammation><neural signaling><neurobehavioral><neurobiological><neurodegeneration><neurodegenerative><neurodegenerative illness><neuroinflammation><neuroinflammatory><neurological degeneration><neuronal degeneration><neuronal signaling><neuropathologic tau><neuropathological tau><neurotransmission><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><non-medical opioid use><nonmedical opioid use><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><opiate consumption><opiate crisis><opiate drug use><opiate intake><opiate misuse><opiate use><opiate use disorder><opioid addiction><opioid consumption><opioid crisis><opioid dependence><opioid dependent><opioid drug use><opioid epidemic><opioid intake><opioid misuse><opioid use><opioid use disorder><overdose death><overdose fatalities><overexpress><overexpression><p-tau><p-τ><pain killer><pain medication><pain reliever><pain treatment><painkiller><paired helical filament of tau><patch clamp><pathophysiology><perivascular glial cell><phospho-tau><phospho-τ><phosphorylated tau><post-translational modification of tau><postmortem><posttranslational modification of tau><pre-clinical study><preclinical study><preference><primary degenerative dementia><protein blotting><self-aggregate tau><senile dementia of the Alzheimer type><service availability><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><social role><success><synapse><synapse function><synaptic function><tau><tau PHF><tau Proteins><tau accumulation><tau aggregate><tau aggregation><tau associated neurodegeneration><tau associated neurodegenerative process><tau expression><tau factor><tau fibrillization><tau filament><tau induced neurodegeneration><tau mediated neurodegeneration><tau neurodegenerative disease><tau neurofibrillary tangle><tau neuropathology><tau oligomer><tau paired helical filament><tau phosphorylation><tau polymerization><tau posttranslational modification><tau-1><tau-tau interaction><tauopathic neurodegenerative disorder><tauopathy><transmission process><treatment access><treatment effect><vector><wildtype mouse><γ-Aminobutyric Acid><τ Proteins><τ aggregation><τ expression><τ phosphorylation>