# Enduring enhancement of neuropathic pain by early post-trauma morphine

> **NIH NIH R01** · UNIVERSITY OF COLORADO · 2021 · $530,422

## Abstract

Project Summary
 Opioids are widely used to treat pain after trauma. Opioid use for pain management has dramatically in-
creased, with little assessment of potential negative consequences for ongoing pain. Recent reports are critical
of the lack of controlled, long-term studies to support the dramatic escalation of opioid treatment for chronic
pain over the past decade. While one long-term concern is that there may be no benefit, another is that opioids
could have negative consequences for pain. There would be major implications were opioid treatment to pro-
long the course of pain long after opioid cessation. As described in this proposal, robust opioid-induced chroni-
fication of pain does indeed occur, making this a phenomenon critical to understand.
 Disturbingly, we have discovered that opioids given around the time of trauma may be contraindicated: a
brief course of treatment with morphine (5 mg/kg b.i.d. for 5-7 days) can amplify the magnitude and duration of
neuropathic pain for months thereafter. Strikingly, this deleterious opioid effect occurs across all models tested
to date: inflammatory pain, peripheral and central neuropathic pain, and post-operative pain, supportive that
this is a widespread phenomenon worthy of study. This unanticipated effect of morphine across time and di-
verse pain models had not been previously reported. Beyond our initial studies, nothing is known regard-
ing the spinal mechanistic underpinnings of this multi-month exaggeration of neuropathic pain by a
brief exposure to morphine restricted to the early post-trauma period.
 Three Aims are proposed. All studies are undertaken in both sexes, given that documented male/female
differences in immune and glial function, neuropathic pain, and responses to opioids, suggest that distinct un-
derlying mechanisms will likely be found across sexes. The first Aim examines how a short course of morphine
in the early post-trauma period functionally modifies the neuroimmunology of the ipsilateral lumbar dorsal spi-
nal cord and discovers which of these changes mediate pain enhancement. The second Aim utilizes state-of-
the-art Robust Activity Marking (RAM) technologies in spinal cord to address how identified mediators of mor-
phine-induced pain enhancement align with retrogradely labeled spinothalamic neurons with defined activation
state. The third Aim examines supraspinal mechanisms contributing to morphine-induced chronification of neu-
ropathic pain. Aim 3 utilizes state-of-the-art DREADD reversible inactivation of microglia vs. excitatory neurons
to define the role of the caudal granular insular cortex (CGIC), which we have previously shown (in the ab-
sence of early post-trauma morphine) to be critical to chronic pain maintenance. Here we will reversibly inhibit,
in a cell-type targeted fashion, either microglia or excitatory neurons in CGIC either only during morphine dos-
ing or only during the period of morphine-induced chronification of pain to define CGIC involv...

## Key facts

- **NIH application ID:** 10142406
- **Project number:** 5R01DA044934-04
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** LINDA WATKINS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $530,422
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10142406

## Citation

> US National Institutes of Health, RePORTER application 10142406, Enduring enhancement of neuropathic pain by early post-trauma morphine (5R01DA044934-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10142406. Licensed CC0.

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