# Defining a role for kappa opioid system in affective behavior and drug escalation in pain

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $346,261

## Abstract

Pain and reward are considered opponent processes but are processed within overlapping brain structures. It
has been demonstrated that rewarding stimuli can decrease pain sensitivity, whereas pain can impair reward
processing leading to an anhedonic state. However, it is not yet known how the presence of pain modifies the
reinforcing properties of natural rewards and opioids. The mesolimbic pathway is a critical brain nuclei that is
altered in opioid addiction making it an ideal neural circuit to investigate the mechanistic basis for opioid abuse
in the presence of pain. Opioid-induced released of dopamine (DA) in the nucleus accumbens (NAc)
contributes to their abuse potential, where an allostatic shift in reward signaling leads to the pathological state
of addiction. Mu opioid receptor (MOPR) agonists are positively reinforcing and remain the predominant
opioids used for clinical and recreational-abuse purposes. In contrast, the activation of brain kappa opioid
receptors (KOPR) causes dysphoria via suppression of mesolimbic DA and 5HT activity within the nucleus
NAc reward circuitry. It is thought that these two opposing opioid-receptor systems work together to partially
maintain the balance of affective state, however dysregulation of one or the other system can lead to dramatic
changes in reward processing behaviors. We recently reported that persistent inflammatory pain negatively
impacts function of MOPR in the ventral tegmental area (VTA) with a concomitant loss of mu-opioid-induced
DA release in the NAc which may partially underlie the observed increase in the intake of very high doses of
the opioid. Interestingly, our initial findings indicate that persistent inflammatory pain enhances KOPR function
in the NAc, promoting negative affect states (i.e. decrease in the overall motivational state and enhanced
aversive behavior) which may be crucially involved in driving increased opioid consumption when high doses
are accessible, as recently proposed to maintain drug seeking and escalation of intake. Taken together, these
preliminary findings strongly support the central hypothesis of this multidisplinary proposal that pain reduces
the activity of the VTA-NAc dopamine reward circuit, via an enhancement of the dynorphin-KOPR system
activity to decrease motivation and promote dysphoria. We hypothesize that this pain-induced KOPR-mediated
negative affective state drives the intake of high dose opioids leading to misuse and drug escalation. Using a
series of multidisplinary approaches including electrophysiology, microdialysis, voltammetry, optogenetics,
chemogenetics, mouse genetics, and rodent PET imaging tools, we propose to determine whether in vivo
manipulation of dynorphin-KOPR system in the VTA-NAc circuit prevents pain-induced negative affect which
drives opioid dose escalation.

## Key facts

- **NIH application ID:** 10220002
- **Project number:** 5R01DA045463-04
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Jose A Moron-Concepcion
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $346,261
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10220002

## Citation

> US National Institutes of Health, RePORTER application 10220002, Defining a role for kappa opioid system in affective behavior and drug escalation in pain (5R01DA045463-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10220002. Licensed CC0.

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