# 5-HT3 receptor antagonists for neuropathic pain

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $437,180

## Abstract

Project Summary / Abstract
 Neuropathic pain (NeuP) affects >16 million Americans and results in considerable impairment in quality of
life. Available medications fail to adequately relief pain in the majority of NeuP patients; moreover, efficacious
drugs such as opioids have major safety concerns. Therefore, new therapeutic approaches are urgently
needed. Serotonergic 5-HT3 receptors (5-HT3R) have been identified as a promising pharmacological target in
NeuP. After peripheral nerve damage, overexpression of 5-HT3 receptors in spinal cord neurons can shift the
character of descending serotonergic modulation from inhibitory to facilitatory, thus contributing to ongoing
pain. Intrathecal 5-HT3R antagonists alleviate evoked hypersensitivity in animal NeuP models, but the
analgesic effects are inconsistent with systemic administration of these drugs in patients with neuropathic pain.
Our preliminary data suggest that efflux transporters such as the P-glycoprotein (Pgp) limit the central nervous
system (CNS) exposure of 5-HT3R antagonists, thus preventing analgesia following systemic administration.
 We hypothesize that if 5-HT3R antagonists were to reach adequate CNS concentrations, they would be
efficacious in relieving neuropathic pain. To validate 5-HT3R as a clinically-relevant drug target in neuropathic
pain, we plan to undertake the following translational approach:
1) We will characterize the CNS disposition of model 5-HT3R antagonsits ondansetron and granisteron in a rat
model, and determine the effect of efflux transporters such as Pgp on their CNS disposition. This will be done
by a) determining drug bio-disposition in rat plasma and cerebrospinal fluid (CSF), as well as in brain and
spinal cord (whole tissue analysis and micro-dialysis), and b) utilizing genetic and pharmacological knockouts
of Pgp transporters to determine the effects of efflux transporters on drug disposition.
2) We will determine the role of Pgp efflux on ondansetron disposition in human CNS. This will be done by
detemining the time-course of plasma and CSF concentrations of IV ondansetron in healthy subjects, with and
without tariquidar– a selective inhibitor of Pgp transporters. Analgesia will be assessed in an experimental pain
model, and physiologically-based pharmacokinetic modeling will be implemented to predict ondansetron
concentrations in human brain and spinal cord, based on combined results from animal and human studies.
3) We will determine the effect of adequately CNS-penetrating ondansetron on neuropathic pain. In an
experimental cross-over study in NeuP patients, analgesia will be compared when ondansetron is administered
with and without tariquidar. In an exploratory mechanism-based analysis, we will determine the association
between the extent of individual descending pain facilitation and the analgesic response to 5-HT3R blockade.
 We expect the results to successfully determine the mechanisms limiting CNS exposure of 5-HT3R
antagonists, and to demonst...

## Key facts

- **NIH application ID:** 9869947
- **Project number:** 5R01NS104500-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Simon Haroutounian
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $437,180
- **Award type:** 5
- **Project period:** 2018-02-15 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9869947

## Citation

> US National Institutes of Health, RePORTER application 9869947, 5-HT3 receptor antagonists for neuropathic pain (5R01NS104500-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9869947. Licensed CC0.

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