# p38 MAPK Mechanisms of Kappa Opioid-Induced Behaviors

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2020 · $340,898

## Abstract

Project Summary: Pharmacological activation of kappa opioid receptors (KOR) in humans elicits reports of
dysphoria and cognitive disruption. KOR activation in rodents by agonists or by stress-evoked dynorphin
release have been shown to produce aversion, increase anxiety-like behaviors, increase the rewarding effects
of drugs of abuse (e.g. cocaine, ethanol & nicotine), increase addictive drug self-administration, and reinstate
extinguished drug-seeking behaviors. The cellular and molecular mechanisms responsible for these dynorphin-
dependent, pro-addictive behaviors are not fully understood, and a better understanding may suggest new
therapeutic approaches to the treatment and prevention of stress-related diseases including some forms of
drug addiction. Prior studies supported by this award demonstrated that KOR activation by stress-induced
release of dynorphin or pharmacological KOR agonist administration produces aversion in mice and
potentiates cocaine conditioned place preference by activating p38α MAPK in serotonergic and dopaminergic
neurons to regulate excitability and serotonin transport. Conditional knockout of p38α MAPK in either
serotonergic neurons of the dorsal raphe or dopaminergic neurons in the ventral tegmental area (VTA),
blocked the aversive and pro-addictive effects of KOR activation. It is not yet clear how KOR regulation of the
serotonergic, glutamatergic, and dopaminergic circuits individually contribute to the behaviors, and the studies
proposed in this renewal are designed to better define how dynorphin regulation of each of these neural
circuits results in the dysphoric and pro-addictive effects of stress. To accomplish these aims, we propose to:
1) use optogenetic activation and inhibition of dorsal raphe neurons that project to nucleus accumbens or VTA
to define the circuits and mechanisms responsible for dynorphin-dependent, stress-induced potentiation of
cocaine place preference; 2) identify the sources of dynorphin responsible for these behavioral effects by
excising prodynorphin in pDynflox mice from candidate neurons then assessing the effects on stress-induced
potentiation of cocaine place preference; 3) use whole cell voltage clamp recordings of VTA dopamine neurons
to characterize the pre and postsynaptic effects of KOR activation of p38α MAPK, which has been previously
shown to be required for these stress-induced behaviors. Kappa opioid receptor antagonists may have
therapeutic potential in the treatment of addiction by promoting stress resilience, and the proposed studies
would advance that concept by defining the actions of stress-induced dynorphin on the reward circuit.
Functionally selective kappa opioid receptor agonists that activate G-protein signaling without stimulating p38α
MAPK may be effective analgesics without producing the euphorigenic effects of mu opioid agonists or the
dysphoric effects of conventional kappa agonists. The proposed studies would advance our understanding of
the therapeutic p...

## Key facts

- **NIH application ID:** 9933868
- **Project number:** 5R01DA030074-10
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Charles Chavkin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $340,898
- **Award type:** 5
- **Project period:** 2011-03-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9933868

## Citation

> US National Institutes of Health, RePORTER application 9933868, p38 MAPK Mechanisms of Kappa Opioid-Induced Behaviors (5R01DA030074-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9933868. Licensed CC0.

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