# Pharmacology of Kappa Opioid Receptor

> **NIH NIH R01** · TEMPLE UNIV OF THE COMMONWEALTH · 2021 · $538,986

## Abstract

Opioid receptors (µ, d and k), are Gi/o-coupled, rhodopsin-like receptors. κ opioid receptor (KOPR) agonists may be useful
as analgesics and antipruritic agents without abuse potential and respiratory depression associated with currently use µ
opioid analgesics. However, prototypic selective KOPR agonists cause dysphoria or aversion, which limits their
development. G protein-coupled receptors (GPCRs) signal via both G protein or arrestin to activate different downstream
effectors. Biased agonists preferentially activate G protein- or arrestin-mediated signaling and thus may have advantages
over balanced or unbiased agonists in that they may produce therapeutic effects with fewer side effects. However,
translating in vitro ligand bias to in vivo pharmacology has been uncertain. Nalfurafine, the only selective KOPR agonist
in clinical use, is prescribed in Japan for treatment of uremic pruritus, without causing dysphoria at therapeutic doses. In
mice, we observed that nalfurafine caused conditioned place aversion (CPA) at doses higher than the effective doses for
the antinociceptive and anti-scratch effects; however, the reverse was true for two other selective KOPR agonists,
U50,488H and MOM-SalB. Similarly, U50,488H, but not nalfurafine, induced anhedonia. Thus, we established an animal
model to understand the mechanisms underlying separation of anti-pruritic and analgesic effects from dysphoria / aversion
of KOPR agonists. Importantly, we found in mouse brains U50,488H and MOM-SalB caused robust KOPR
phosphorylation, but nalfurafine did not. Also,U50,488H, but not nalfurafine, enhanced phosphorylation of some proteins
downstream of mTOR and the mTOR pathway may be involved in KOPR-mediated CPA. For Specific Aim 1, We will
test the hypothesis that the ability of agonists to promote CPA is related to its ability cause KOPR phosphorylation by
examining several structurally distinct KOPR agonists. KOPR phosphorylation will be detected with immunoblotting
using our own antibodies that specifically recognize phosphorylated KOPR. For Specific Aim 2, we will examine the
differences between U50,488H and nalfurafine in downstream phosphoproteomic changes in brain regions important in
KOPR pharmacology. Furthermore, we will investigate the involvement of differentially regulated proteins / pathways in
KOPR-mediated CPA and anhedonia. For Specific Aim 3, we will generate mutant mouse lines to examine the roles of
agonist-promoted KOPR phosphorylation and GRK5 and GRK6 in KOPR pharmacology in vivo. KOPR-mediated
antipruritic, antinociceptive, aversive and sedative effects and motor incoordination will be used as the in vivo
pharmacological measures. Our “from bedside to bench” approach, distinctly different from the commonly used “from
bench to bedside” strategy, allows us to circumvent the challenges of translating in vitro cell-based results to in vivo
pharmacology. Taken together, the proposed studies will greatly advance our understanding of KOPR pharmac...

## Key facts

- **NIH application ID:** 10212993
- **Project number:** 5R01DA041359-05
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** LEE-YUAN LIU-CHEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $538,986
- **Award type:** 5
- **Project period:** 2017-09-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10212993

## Citation

> US National Institutes of Health, RePORTER application 10212993, Pharmacology of Kappa Opioid Receptor (5R01DA041359-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10212993. Licensed CC0.

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