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Principal Investigator: Mark L Baccei
Organization: UNIVERSITY OF CINCINNATI
Fiscal Year: 2024
Award: $575,744
Funding agency: National Institute of Neurological Disorders and Stroke
Project Summary/Abstract
Long-term potentiation (LTP) of primary afferent synapses onto spinal projection neurons (PNs) has
been linked to increased pain sensitivity. The timing rules controlling the generation of LTP in adult PNs can
be persistently relaxed by neonatal tissue damage, which likely contributes to the ability of early life injury to
‘prime’ nociceptive circuits and thereby exacerbate pain after subsequent insult. In the brain, the temporal
window governing this spike timing-dependent plasticity (STDP) is strongly regulated by G protein-coupled
receptor (GPCR) signaling evoked by neuromodulators such as dopamine (DA). This raises the possibility that
neonatal injury facilitates LTP at primary afferent synapses onto adult PNs, and thereby promotes persistent
pain, via long-term changes in spinal neuromodulatory signaling. Unfortunately, it remains unknown how
GPCRs influence STDP at sensory synapses onto PNs. As a result, the cellular and molecular mechanisms
underlying the increased amplification of ascending nociceptive transmission by the adult dorsal horn during
the primed state are poorly understood. The objective of this application is to identify the neuromodulatory
signals that promote the activity-dependent strengthening of sensory synapses onto the key output neurons of
the spinal nociceptive circuit and contribute to the priming of developing pain pathways after early life injury.
The central hypothesis is that ‘non-Hebbian’ LTP at sensory synapses onto spinal PNs is enabled by D1-like
(i.e. D1/D5) dopamine receptor activation, occurring in concert with mGluR5-dependent intracellular Ca2+
release and extracellular signal-regulated kinase (ERK) signaling, which is essential for neonatal priming. The
rationale of the proposed research is that these studies will identify novel molecular strategies to reduce the
signaling gain of the spinal nociceptive network. Guided by strong preliminary data, the central hypothesis will
be tested by pursuing the following specific aims: (1) Elucidate how DA receptor activation shapes STDP in
PNs; (2) Identify the signaling pathways which cooperate with DA receptors to facilitate LTP in PNs; and (3)
Identify the neuromodulators which mediate the priming of spinal nociceptive circuits following neonatal tissue
damage. These aims will be accomplished by using a multidisciplinary experimental approach that includes
electrophysiological characterization of STDP in PNs combined with both reflexive and non-reflexive behavioral
measures of pain. The proposed work is innovative because it will be the first to demonstrate that DA signaling
dictates the timing rules governing the plasticity of sensory synapses onto spinal PNs. The outcome of these
investigations will be the identification of new spinal mechanisms that augment nociceptive transmission to the
brain, and the demonstration that aberrant neuromodulation contributes to the persistent sensitization of spinal
nociceptive circuits after early tissue damage. Thus the proposed research is significant because it will provide
knowledge needed to design novel interventional strategies to disrupt spinal LTP as a means to alleviate
chronic pain and to minimize the long-term consequences of neonatal tissue injury for the developing CNS.
Terms: <0-11 years old><21+ years old><Adult><Adult Human><Agonist><Analgesia Tests><Body Tissues><Brain><Brain Nervous System><Cell Communication and Signaling><Cell Signaling><Child><Child Youth><Children (0-21)><Data><Dopamine><Dopamine Receptor><Drugs><E-stim><ERK 1><ERK MAP Kinases><ERK1><ERK1 Kinase><Electric Stimulation><Electrophysiology><Electrophysiology (science)><Encephalon><Environment><Extracellular Signal Regulated Kinases><Extracellular Signal-Regulated Kinase 1><Extracellular Signal-Regulated MAP Kinases><Fostering><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G Protein-Coupled Receptor Signaling><G-Protein-Coupled Receptors><GPCR><GPCR Signaling><GRIK1 gene product><Generations><Genetic><Human><Hydroxytyramine><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><In Situ Hybridization><In Vitro><Infant><Injury><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Investigation><Knowledge><Learning><Life><Link><Long-Term Potentiation><Longterm Potentiation><MAP Kinase 3><MAPK ERK Kinases><MAPK3><MAPK3 Mitogen-Activated Protein Kinase><MAPK3 gene><Mediating><Medication><Mice><Mice Mammals><Mitogen-Activated Protein Kinase 3><Mitogen-Activated Protein Kinase 3 Gene><Modern Man><Molecular><Murine><Mus><Neonatal><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neuromodulator><Neurons><Neurophysiology / Electrophysiology><Nociception><Nociception Tests><Otomy><Outcome><Output><P44ERK1><PSTkinase p44mpk><Pain><Pain Assessment><Pain Measurement><Pain measure><Painful><Pathway interactions><Persistent pain><Pharmaceutical Preparations><Protocol><Protocols documentation><Public Health><Receptor Activation><Receptor Protein><Regulation><Relaxation><Research><Rodent><Rodentia><Rodents Mammals><Sensory><Shapes><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Spinal><Surgical Injuries><Surgical incisions><Synapses><Synaptic><Synaptic plasticity><Testing><Threonine/Tyrosine Protein Kinase><Time><Tissues><Transmission><Work><adulthood><antagonism><antagonist><behavior measurement><behavioral measure><behavioral measurement><biological signal transduction><chronic pain><constant pain><design><designing><dorsal horn><drug/agent><druggable target><electrophysiological><electrostimulation><extracellular signal related kinase><gene manipulation><genetic manipulation><genetically manipulate><genetically perturb><in situ Hybridization Genetics><in situ Hybridization Staining Method><incision><inhibitor><injuries><injury to tissue><innovate><innovation><innovative><insight><interventional strategy><kids><lasting pain><metabotropic glutamate receptor 5><multidisciplinary><neonatal injury><neonatal surgery><neural control><neural regulation><neuromodulation><neuromodulatory><neuronal><neuroregulation><nociceptive><novel><on-going pain><ongoing pain><p44 MAPK><pain assay><pain perception><pain sensation><pain sensitivity><painful sensation><pathway><permissiveness><pharmacologic><postsynaptic><presynaptic><prevent><preventing><receptor><synapse><tissue injury><transmission process><youngster>