# Traumatic Brain Injury and Endogenous Pain Modulation

> **NIH VA I01** · VETERANS ADMIN PALO ALTO HEALTH CARE SYS · 2020 · —

## Abstract

Chronic pain and disability after war-related injuries and after trauma sustained in civilian settings are
unexpectedly common. Chronic pain related to traumatic brain injury (TBI) in combination with peripheral
injuries is particularly problematic, and we have no well-validated treatments. Potentially explaining the TBI-
chronic pain relationship, data from both humans and animal models suggest that descending pain
modulation is disrupted after TBI. Recently collected data using laboratory models of brain injury and TBI
patients demonstrate the vulnerability of brainstem centers governing endogenous pain modulation.
Histopathological and functional TBI studies suggest damage to the periaqueductal gray matter (PAG), a
major endogenous pain control center, and the locus coeruleus (LC), a key structure providing descending
noradrenergic inhibition to the spinal cord. Moreover, TBI alters the function of the rostral ventromedial
medulla (RVM), a structure that provides both descending pain-facilitating and pain-inhibiting serotonergic
fibers. Our main objective is, therefore, to evaluate endogenous pain regulatory mechanisms after TBI and
pre-clinically test translatable approaches to pain control in this setting.
 In the first aim we evaluate the hypothesis that TBI disrupts descending pain modulation by altering
descending noradrenergic and serotonergic circuits. The experimental approach uses a well-validated rat
fluid percussion model of TBI studied along a broad time course to mimic sub-acute and chronic injuries.
Highly selective and clinically available pharmacological tools targeting noradrenalin release, serotonergic
tone and the stimulation of α2-adrenergic, as well as 5-HT3 and 5-HT7 receptors will be employed.
Outcomes will focus on the regulation of nociceptive thresholds and the efficiency of descending pain
modulation circuits.
 In the second aim we evaluate the hypothesis that TBI injures neurons and promotes sustained neuro-
inflammation in the LC and RVM as well as giving rise to functional changes in descending pain modulation.
In addition to neuropathological evaluations of brainstem and spinal tissues, we will use the microinjection
of selective neurotoxins and chemogenetic DREADDs to study the function of brainstem pain regulatory
centers after TBI.
 In the final aim we use two models of polytrauma combining TBI with soft tissue incision and, separately,
tibial fracture. We hypothesize that clinically available modulators of noradrenergic and serotonergic
signaling will reduce nociceptive sensitization, enhance descending pain modulation and reduce the
interaction of peripheral trauma and TBI on neuroinflammation and the expression of several pain-related
spinal genes. By reducing chronic pain-related changes we further hypothesize that functional measures,
anxiety and cognitive changes will all be less affected after the injuries.
 At the time of completion of the project we expect to understand better how TBI, peripheral inju...

## Key facts

- **NIH application ID:** 9941391
- **Project number:** 2I01RX001776-05
- **Recipient organization:** VETERANS ADMIN PALO ALTO HEALTH CARE SYS
- **Principal Investigator:** DAVID J. CLARK
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2016-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9941391

## Citation

> US National Institutes of Health, RePORTER application 9941391, Traumatic Brain Injury and Endogenous Pain Modulation (2I01RX001776-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9941391. Licensed CC0.

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