# Cellular, synaptic, and network adaptations of MCL addiction and motivation circuits (NAc, VTA, PAG) with chronic pain and opioid exposure

> **NIH NIH P50** · NORTHWESTERN UNIVERSITY · 2020 · $311,418

## Abstract

Chronic pain is the top source of disability in the U.S. and is commonly treated with opiates. Many chronic pain patients
given prescription opiates for treatment struggle with addiction and the abuse of opioids has reached epidemic
proportions in the U.S. The neurobiological basis for the connection between chronic pain and opioid abuse is
uncertain. However, recent work has shown that chronic pain is shaped by the same mesolimbic circuitry underlying
drug addiction. The ventral tegmental area (VTA) and nucleus accumbens (NAc) appears to be critical hubs of this
circuitry. Their role in drug addiction is well-established. What is new is that they also play key roles in chronic pain. We
have shown that in the rodent spared nerve injury (SNI) model of chronic pain there are cell-specific and region-specific
adaptations in the NAc that include both intrinsic and synaptic changes. These changes were causally linked to pain
behavior and alterations in the activity of dopaminergic neurons in the VTA. Although there are clear effects of opioids
on the VTA and NAc, how opioids shape SNI-induced adaptations in the NAc is completely unexplored. Moreover, it is
unclear how chronic pain modifies the addictive potential of opioids. In Project 2, our over-arching goal is to fill these
gaps in our understanding. To this end, an array of modern behavioral, anatomical, physiological and molecular
approaches will be used in mouse models to achieve four specific aims: Specific Aim 1: To determine whether morphine
reinforcement and seeking behavior is enhanced in SNI mice trained to self-administer morphine. Our working hypothesis
is that SNI will increase the reinforcing efficacy of morphine and drug seeking behavior. Specific Aim 2: To determine
whether SNI differentially affects VTA DA neurons innervating the medial shell and core of the NAc and whether these
effects are modulated by morphine self-administration (MSA). Our working model is that VTA regions innervating the
msNAc and cNAc are non-overlapping and respond in largely opposing ways to SNI. Moreover, we hypothesize that
short-term MSA will diminish SNI-induced adaptations. Specific Aim 3: To determine whether short-term (5d) morphine
self-administration alters SNI-induced adaptations in specific NAc circuits. Our working hypothesis is that MSA shortly
after SNI will dampen ascending nociceptive signaling and attenuate alterations in the activity of VTA, resulting in only
modest adaptations in msNAc/cNAc circuits. Specific Aim 4: To determine whether long-term (14 d) morphine self-
administration and withdrawal alters SNI induced adaptations in specific NAc circuits. Our working hypothesis is that
with time the beneficial effects of morphine on VTA and NAc circuits will wane, leading to augmentation of SNI-induced
adaptations in NAc circuits, resulting in enhanced morphine reward and drug seeking. The studies outlined for these four
aims should provide fundamental new insights into the mechanisms by whi...

## Key facts

- **NIH application ID:** 9938530
- **Project number:** 5P50DA044121-03
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** DALTON JAMES SURMEIER
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $311,418
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9938530

## Citation

> US National Institutes of Health, RePORTER application 9938530, Cellular, synaptic, and network adaptations of MCL addiction and motivation circuits (NAc, VTA, PAG) with chronic pain and opioid exposure (5P50DA044121-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9938530. Licensed CC0.

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