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Principal Investigator: Gregory Scherrer
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2024
Award: $705,382
Funding agency: National Institute of Neurological Disorders and Stroke
PROJECT SUMMARY
Pain is a multidimensional experience with sensory and affective components. The aversive quality of pain, i.e.
its inherent unpleasantness, causes a majority of chronic pain patients’ suffering and often leads to comorbid
disorders such as anxiety and depression. Despite their addictive qualities, opioid analgesics remain clinically
useful since they can profoundly dampen pain affect. Thus, discovering targets that could alter neural activity
selectively in neural circuits that generate pain aversion, but not in the reward or breathing circuits that opioids
also alter, is an attractive strategy to develop novel, safer analgesics.
Recently, by combining in vivo imaging and chemogenetic manipulations of neural dynamics in the basal
and lateral amygdala (BLA) of freely behaving mice encountering noxious stimuli, our collaboration discovered
a distinct neural ensemble in the BLA that encodes the negative affective valence of pain (Corder et al., Science,
2019). Chemogenetic inhibition of this nociceptive coding ensemble using Gi/o-protein-coupled-DREADDs
alleviated pain affective behaviors without altering withdrawal reflexes, anxiety or reward. Moreover, our
functional studies of this nociceptive ensemble revealed its causal role in the phenomenon of allodynia.
Based on these exciting findings, we now seek to identify novel targets to treat pain by determining the
molecular identity of these BLA nociceptive cells via in situ hybridization and single cell RNA-sequencing
(scRNA-seq). Our preliminary scRNA-seq studies of BLA nociceptive cells suggest they express dozens of Gi/o
protein-coupled receptors (Gi/o-GPCRs) that could be targeted for anti-nociception against pain affect. Further,
our tracing studies have revealed a set of layer V pyramidal cells in anterior cingulate cortex (ACC) that project
onto BLA nociceptive neurons, consistent with the fact cingulotomy can be used to treat intractable chronic pain.
Resolving the molecular identity of these ACC nociceptive cells could also reveal new targets to treat pain affect.
Thus, here we propose to catalog candidate Gi/o-GPCR targets in BLA and ACC (Aim 1, Discovery), test
their utility to treat pain (Aim 2, Validation), and verify these new targets have no effect in the brain’s reward and
breathing circuitry (Aim 3, Safety & Translatability). In Aim 1 we will identify Gi/o-GPCR targets in pain affect
circuits of the BLA and ACC using mouse genetics, viral tracers, scRNA-seq and bioinformatics analyses. In
Aim 2, we will validate the neurophysiological effects and analgesic properties of these new targets, using
electrophysiological recordings in live brain tissue slices, animal models of acute and chronic pain, and Ca2+
imaging studies in behaving mice of BLA and ACC neural activity. In Aim 3, we will verify the safety and
translatability of the novel antinociceptive drug targets. We will evaluate each target for abuse potential and
effects on breathing by using behavioral assays for reward processing and whole-body plethysmography,
respectively. To evaluate whether our results in rodents are likely to translate clinically, we will also analyze
expression patterns of the drug targets in human tissue using in situ hybridization.
Terms: <Acute Pain><Affect><Affective><Agonist><Allelism Test><American><Amygdala><Amygdaloid Body><Amygdaloid Nucleus><Amygdaloid structure><Analgesic Agents><Analgesic Drugs><Analgesic Preparation><Analgesics><Animal Model><Animal Models and Related Studies><Animals><Anodynes><Anterior><Antinociceptive Agents><Antinociceptive Drugs><Anxiety><Area><Behavior><Behavioral Assay><Bio-Informatics><Bioinformatics><Brain><Brain Nervous System><Breathing><Catalogs><Cell Body><Cells><Clinical><Code><Coding System><Collaborations><Complementation Test><Coupled><DREADDs><Dimensions><Disease><Disorder><Dissociation><Drug Modulation><Drug Targeting><Drugs><Electrophysiology><Electrophysiology (science)><Emotional><Emotions><Encephalon><FISH Technic><FISH Technique><FISH analysis><FISH assay><Fluorescence Activated Cell Sorting Fractionation><Fluorescence In Situ Hybridization><Fluorescence-Activated Cell Sorting><Fluorescence-Activated Cell Sortings><Fluorescent in Situ Hybridization><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G-Protein-Coupled Receptors><GPCR><Genetic><Genetic Complementation Test><Genomics><HEAL Initiative><Helping End Addiction Long-term><Helping End Addiction Longterm><Helping to End Addiction Long-term><Helping to End Addiction Longterm><Human><In Situ Hybridization><Label><Lateral><Light><Mechanics><Mediating><Medication><Mental Depression><Methods><Mice><Mice Mammals><Modern Man><Molecular><Monitor><Murine><Mus><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Neurophysiology / Electrophysiology><Nociception><Nociceptors><Non-Polyadenylated RNA><Opiate Receptors><Opiates><Opioid><Opioid Analgesics><Opioid Receptor><Pain><Pain quality><Painful><Pathway interactions><Patients><Pattern><Peripheral nerve injury><Pharmaceutical Preparations><Photoradiation><Population><Property><Proteins><Pyramidal Cells><Pyramidal neuron><RNA><RNA Gene Products><Receptor Protein><Reflex><Reflex action><Reporting><Research><Respiratory Aspiration><Respiratory Inspiration><Rewards><Ribonucleic Acid><Rodent><Rodentia><Rodents Mammals><Role><SRIH Receptors><SSTR2><SSTR2 gene><Safety><Science><Sensory><Shapes><Slice><Somatostatin Receptor><Somatotropin Release Inhibiting Hormone Receptors><Stimulus><Testing><Tracer><Trans Test><Translating><Validation><Viral><Visualization><Whole Body Plethysmography><Wild Type Mouse><Withdrawal><abuse liability><abuse potential><allodynia><amygdaloid nuclear complex><antinociception><antinociceptive><brain tissue><catalog><cell cortex><chronic pain><chronic pain patient><cingulate cortex><cingulotomy><co-morbid><co-morbidity><comorbidity><complementation analysis><complementation approach><depression><designer receptors exclusively activated by designer drugs><dosage><drug/agent><electrophysiological><experience><gene manipulation><genetic manipulation><genetically manipulate><genetically perturb><hippocampal pyramidal neuron><human tissue><imaging in vivo><imaging study><in situ Hybridization Genetics><in situ Hybridization Staining Method><in vivo><in vivo imaging><inspiration><mechanic><mechanical><model of animal><mouse genetics><negative affect><negative affectivity><neural><neural circuit><neural circuitry><neurocircuitry><neuronal><neuropathic pain><neurophysiological><neurophysiology><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><nociceptive><nociceptive neurons><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><opiate analgesia><opiate analgesic><opiate pain medication><opiate pain reliever><opioid analgesia><opioid anesthetic><opioid pain medication><opioid pain reliever><opioid painkiller><pain killer><pain medication><pain patient><pain relief><pain reliever><pain-sensing neurons><pain-sensing sensory neurons><pain-sensing somatosensory neurons><painful neuropathy><painkiller><pathway><patient with chronic pain><peripheral nerve crush injuries><promoter><promotor><receptor><relieve pain><response><reward processing><scRNA-seq><side effect><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><spontaneous pain><synaptic circuit><synaptic circuitry><validations><wildtype mouse>