# Evaluation of drug mixtures for treating pain: behavioral and pharmacological interactions between opioids and serotonin agonists

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2021 · $404,601

## Abstract

PROJECT SUMMARY
Opioids remain the gold standard for treating moderate to severe pain, but their use is limited by numerous
adverse effects including tolerance, dependence, abuse, and overdose. Adverse effects could be avoided by
combining an opioid with another drug, such that smaller doses of the opioid (in combination with another drug)
produce the desired therapeutic effect. Direct-acting serotonin type 2 (5-HT2) receptor agonists interact in a
synergistic manner with the opioid morphine to produce antinociceptive effects, suggesting a 5-HT2 receptor
agonist could be combined with small dose of an opioid to treat pain thereby lowering the risk associated with
larger doses. However, little is known about interactions between 5-HT2 receptor agonists and other opioids,
and it is unclear whether 5-HT2 receptor agonists enhance other adverse effects, particularly those relating to
abuse or overdose or alter the consequences of repeated treatment with an opioid. Proposed studies evaluate
the therapeutic potential of mixtures of opioids and 5-HT2 receptor agonists using highly translatable and well-
established procedures to characterize the antinociceptive, respiratory-depressant (overdose), positive-
reinforcing (abuse), and discriminative-stimulus (subjective) effects of drug mixtures as well as the impact of
chronic treatment on the development of tolerance to and physical dependence on opioids. Studies in Aim 1
characterize acute interactions between opioids and 5-HT2 receptor agonists for antinociceptive effects and
examine the contribution of 5-HT2 receptor subtypes. Studies in Aim 2 evaluate the acute respiratory-
depressant, positive reinforcing, and discriminative stimulus effects of mixtures containing an opioid and a 5-
HT2 receptor agonist. Studies in Aim 3 compare effects of daily dosing with a mixture of an opioid and a 5-HT2
receptor agonist to those of the opioid administered alone in order to evaluate changes in the development of
tolerance and physical dependence. These studies will identify combinations of opioids and 5-HT2 receptor
agonists that increase the therapeutic window of opioids by decreasing the dose of opioid necessary for
therapeutic effects, while also reducing the adverse effects that currently limit the legitimate medical use of
opioids (tolerance, dependence, abuse and overdose) and 5-HT2 receptor agonists (subjective effects). Using
a species and procedures that are highly translatable to humans, these studies will provide proof-of-concept for
this innovative approach to pain treatment and evaluate the utility of targeting 5-HT receptors for analgesic
drug development.

## Key facts

- **NIH application ID:** 10069360
- **Project number:** 5R01DA046532-03
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** DAVID Richard MAGUIRE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $404,601
- **Award type:** 5
- **Project period:** 2019-02-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10069360

## Citation

> US National Institutes of Health, RePORTER application 10069360, Evaluation of drug mixtures for treating pain: behavioral and pharmacological interactions between opioids and serotonin agonists (5R01DA046532-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10069360. Licensed CC0.

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