# Thalamo-Limbic Circuits in Pain

> **NIH NIH R01** · UNIVERSITY OF CINCINNATI · 2022 · $350,000

## Abstract

Pain tolerance varies widely among peoples and, depending on external and internal circumstances, varies
within an individual from moment to moment. Although the concept of pain tolerance is familiar, the
neurobiological substrates that regulate pain tolerance are unknown. Pain tolerance requires motivational,
emotional, and cognitive processing in addition to the sensory dimension of the pain experience. Achieving an
understanding the specific neurons and circuits in the brain that regulate pain tolerance may to lead to
breakthroughs that will enhance the capacity of patients to cope with intractable pain. This project utilizes
innovative techniques to both assess pain tolerance behavior in animals, and to dissect the neural circuits
thought to regulate pain tolerance. We have discovered that a subtype of pyramidal neuron in limbic cortical
areas including the anterior cingulate cortex and insula becomes hyperexcitable during periods of lowered pain
tolerance produced by injury. These neurons express GRM2, the gene encoding group II metabotropic
glutamate receptors, which is a potential molecular target to control pain tolerance in clinical settings. The
goals of this project are: 1) To identify the thalamo-limbic pathways that regulate pain tolerance; 2) To
determine the role of GRM2 limbic cortical neurons in pain tolerance and nociceptive-withdrawal behaviors,
and, 3) to determine whether pain tolerance can be modulated by pharmacological manipulation of group II
metabotropic glutamate receptors. Optogenetic and pharmacological experiments will be performed in vivo in
mouse to learn whether pain tolerance can be modulated independently of standard nociceptive-withdrawal
thresholds. Modulation of neural activity in models of inflammatory and neuropathic pain will be tested to
determine whether injury-induced changes to pain tolerance can be reversed. Neuro-anatomical and
neurophysiological approaches in vitro will be used to generate new information on the plasticity of the
thalamo-cortical circuits hypothesized to regulate pain tolerance and the membrane biophysics of GRM2
neurons. These experiments will be performed using animal models of persistent pain to determine whether
function and anatomy of thalamo-cortical synapses and GRM2 neurons are altered by pain to provide
mechanistic understanding for behavioral changes in pain tolerance. Pharmacological modulation of group II
mGluR signaling will be tested in vitro to determine the potential for these receptors to be used in future clinical
interventions. Completion of this project will generate new knowledge on the neural systems involved in the
supraspinal processing of pain, including pain tolerance, and potentially catalyze an innovative shift in strategy
for pain relief to enhance coping ability in chronic pain patients through neuromodulation.

## Key facts

- **NIH application ID:** 10397151
- **Project number:** 5R01NS107356-05
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** Steve Davidson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $350,000
- **Award type:** 5
- **Project period:** 2018-06-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10397151

## Citation

> US National Institutes of Health, RePORTER application 10397151, Thalamo-Limbic Circuits in Pain (5R01NS107356-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10397151. Licensed CC0.

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