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Principal Investigator: MARCO MARTINA
Organization: NORTHWESTERN UNIVERSITY AT CHICAGO
Fiscal Year: 2024
Award: $483,395
Funding agency: National Institute of Neurological Disorders and Stroke
Summary
The neurobiological basis of chronic pain is poorly understood and no scientifically validated therapies exist for
such condition. Yet, chronic pain has an enormous socio-economic price, estimated to reach US$ 635 billion
annually in healthcare costs and lost productivity. To make things worse, the majority of opioid abusers begin
their addiction with prescription medications for chronic pain. Consequently, the search for new, non-opioid,
pharmacological treatments for chronic pain constitutes one of the most urgent unmet medical needs. Beside
its sensory symptoms, chronic pain is characterized by impairment of cognitive tasks such as attention and
working memory, which depend on cholinergic modulation of medial prefrontal cortex (mPFC). Accordingly,
mPFC deactivation was found to have a causal role for the neuropathic pain phenotype, and our preliminary
data show that excitatory cholinergic modulation is severely impaired in mPFC pyramidal neurons of male rats.
Yet, the precise mechanisms mediating the mPFC deactivation, how this deactivation influences pain
perception and cognitive performance, and whether it similarly impacts males and females remain largely
unknown. Our preliminary data show that a current mediated by the M1 receptor is critical for mPFC pyramidal
cell excitability and is strongly reduced in neuropathic pain; our overarching hypothesis is that impaired
cholinergic modulation of the mPFC represents a major mechanism of mPFC deactivation in neuropathic pain
and mediates several of the sensory, cognitive and emotional symptoms. In particular, we hypothesize that in
neuropathic pain: (1) cholinergic modulation of mPFC activity is disrupted and this critically contributes to the
global mPFC deactivation in both sexes; (2) blockade of M1-mediated mPFC excitation is sufficient to mimic, at
least in part, the neuropathic pain phenotype; (3) pharmacological manipulations that counterbalance the
cholinergic disruption and restore mPFC output ameliorate cognitive and sensory symptoms of neuropathic
pain. To test these hypotheses we will take advantage of the Spared-Nerve-Injury (SNI) model of neuropathic
pain to pursue two specific aims. In Aim 1 we will combine optogenetic activation of individual cholinergic
inputs, patch clamp recordings in acute slices and PCR analysis, to test the hypothesis that impaired
cholinergic modulation contributes to the global mPFC deactivation, to determine the identity of the receptors
involved, and to dissect the relative impact of cholinergic inputs from local interneurons and from the basal
forebrain on mPFC activity in both females and males. In Aim 2 we will test the behavioral effects of impaired
mPFC cholinergic modulation. We will use in-vivo chemogenetic and pharmacological modulation of the mPFC
to reverse the SNI phenotype. We obtained preliminary data showing that enhancing mPFC excitability through
pharmacological antagonism of the 5HT1a receptor has potent analgesic effects. Conversely, we will also
investigate whether blockade of M1-mediated mPFC excitation in naive animals is sufficient to mimic the SNI
phenotype. Our work will thus identify new potential targets for non-opioid neuropathic pain treatment.
Terms: <ACh Receptors><Acetylcholine><Acetylcholine Receptors><Acute><Affect><Analgesic Agents><Analgesic Drugs><Analgesic Preparation><Analgesics><Animals><Anodynes><Antinociceptive Agents><Antinociceptive Drugs><Attention><Behavior><Behavioral><Biological Function><Biological Process><Cell Communication and Signaling><Cell Signaling><Cholinergic Receptors><Cholinoceptive Sites><Cholinoceptors><Cognitive><Cognitive Disturbance><Cognitive Impairment><Cognitive Manifestations><Cognitive Symptoms><Cognitive decline><Cognitive function abnormal><Common Rat Strains><Connector Neuron><Control Animal><Data><Decision Making><Disturbance in cognition><Drug Delivery><Drug Delivery Systems><Drug Prescribing><Drug Prescriptions><Electrophysiology><Electrophysiology (science)><Emotional><Female><Genetic><Goals><Health Care Costs><Health Costs><Healthcare Costs><High Prevalence><Immediate Memory><Impaired cognition><Impairment><Individual><Intercalary Neuron><Intercalated Neurons><Interneurons><Internuncial Cell><Internuncial Neuron><Intracellular Communication and Signaling><Laboratories><Light><M1 receptor><Medial><Mediating><Medical><Modeling><Molecular><Muscarinic Agents><Muscarinic M1 Receptor><Muscarinics><Nerve Cells><Nerve Unit><Neural Cell><Neurobehavioral Manifestations><Neurobehavioral Signs and Symptoms><Neurobiology><Neurocyte><Neurons><Neurophysiology / Electrophysiology><Opiate abuser><Opiates><Opioid><Opioid abuser><Output><Pain><Pain Control><Pain Therapy><Pain management><Painful><Patients><Pharmacological Treatment><Phenotype><Photoradiation><Position><Positioning Attribute><Prefrontal Cortex><Price><Productivity><Pyramidal Cells><Pyramidal neuron><Rat><Rats Mammals><Rattus><Receptor Protein><Risk><Rodent Model><Role><Sensory><Shapes><Short-Term Memory><Shortterm Memory><Signal Transduction><Signal Transduction Systems><Signaling><Slice><Symptoms><Techniques><Testing><Work><addiction><addictive disorder><antagonism><antagonist><basal forebrain><behavior test><behavioral test><biological signal transduction><cholinergic><chronic pain><chronic pain control><chronic pain intervention><chronic pain management><chronic pain therapy><chronic pain treatment><cognitive dysfunction><cognitive loss><cognitive performance><cognitive task><cost estimate><cost estimation><economic cost><effective therapy><effective treatment><electrophysiological><emotional symptom><hippocampal pyramidal neuron><in vivo><insight><licit opioid><male><medication prescription><nerve injury><neural injury><neurobehavioral symptom><neurobiological><neurobiological mechanism><neuronal><neuropathic pain><non-narcotic analgesic><non-opiate analgesic><non-opioid><non-opioid analgesic><non-opioid therapeutics><nonnarcotic analgesics><nonopiate analgesic><nonopioid><nonopioid analgesics><opiate medication><opioid medication><optogenetics><pain killer><pain medication><pain perception><pain reliever><pain treatment><painful neuropathy><painkiller><patch clamp><pharmacologic><prescribed medication><prescribed opiate><prescribed opioid><prescription opiate><prescription opioid><pricing><receptor><sex><side effect><social role><socio-economic><socio-economically><socioeconomically><socioeconomics><spared nerve><success><treat chronic pain><virtual><working memory>