# Role of SK2 channels in morphine dependence

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $374,464

## Abstract

Although significant advances in the treatment of opiate addiction have been made, relapse to opiate use after
abstinence continues to impede successful treatment, highlighting the need for efforts to dissect the
mechanism of opiate-dependent changes in brain function. Long-lasting associations between opiates and the
context in which they are taken result in cues that lead to drug craving and ultimately relapse. The
hippocampus has traditionally been recognized for its role in learning and memory but recent evidence has
shown its critical role in the behavioral effects of opiates, probably via activation of hippocampal excitatory
inputs to the reward pathway (i.e. Nucleus Accumbens, NAc). Several lines of evidence suggest that drug-
induced contextual/cue memories are associated with molecular changes in hippocampal function and that
these changes may be necessary for some behavioral effects of opiates. Results from our laboratory have
revealed that AMPAR and NMDAR play a crucial role in opiate-induced contextual learning. In addition SK2
channels, which are functionally linked to NMDAR, are critically involved in coding contextual memories.
Furthermore, we have recently found that context-dependent sensitization to morphine leads to the activation
of SK2 channels in the hippocampus. SK2-mediated functional effects on activated spines may be responsible
for the expression and reinstatement of morphine place preference behavior. We also have preliminary data
showing that the intrahippocampal administration of the SK2 blocker, apamin, following conditioning training,
blocks the expression of morphine CPP. However, there are no reports dissecting how SK2 channels influence
learning for opiate-paired contextual/cue behavior. Our central hypothesis is that enhancement of SK2
function, via increased Ca2+ influx through NMDAR, in the hippocampus plays a critical role in the formation of
the association between the drug reward experience and the context/cue. Our overall objective is to uncover
the cellular mechanisms underlying morphine-induced activation of SK2 channels, and to investigate how the
activation of hippocampal SK2 channels are integral for morphine-induced contextual/cue learned
associations, using both the CPP and i.v. drug self-administration models. In Aim 1, we will determine the
mechanisms by which SK2 channel function is increased following morphine contextual/cue associations. In
Aim 2, we will define the requirement for enhanced SK2 channel function in the expression and reinstatement
of morphine contextual/cue associations in vivo. In Aim 3, we will determine whether hippocampal excitatory
inputs to the NAc are enhanced during morphine-contextual/cue associations and to measure the underlying
SK2-mediated changes in hippocampal pyramidal neuronal networks. Studies proposed here offer potentially
novel drug addiction treatments in targeting SK2 channels to prevent drug-context/cue associations and thus
prevent relapse to opiate use...

## Key facts

- **NIH application ID:** 9856427
- **Project number:** 5R01DA042499-04
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Jose A Moron-Concepcion
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $374,464
- **Award type:** 5
- **Project period:** 2017-05-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9856427

## Citation

> US National Institutes of Health, RePORTER application 9856427, Role of SK2 channels in morphine dependence (5R01DA042499-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9856427. Licensed CC0.

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