# Translating Melatonin- and Serotonin-2C Interactions into Improved Treatments for Pain and Opioid-Use Disorders

> **NIH VA I01** · KANSAS CITY VA MEDICAL CENTER · 2020 · —

## Abstract

Background Abuse of opioids is an important problem for the Veterans Health Administration, with serious
medical, psychiatric, social, and economic consequences. Given the increasing prevalence of fatal overdose
and other negative health outcomes associated with opioid abuse, new and innovative treatments are urgently
needed. Melatonin is a hormone and neurotransmitter produced primarily by the pineal gland, which plays a
role in establishing daily and seasonal rhythms. Exogenous melatonin decreases both opioid tolerance and
the severity of withdrawal, which may decrease opioid-reinforced behavior. It also attenuates the expression of
morphine-induced conditioned place preference and decreases cocaine-reinforced behavior. Ramelteon and
agomelatine are potent agonists at melatonin receptors that are structurally related to melatonin and approved
for human use.
Rationale This project will evaluate clinically available melatonin agonists for their effects on opioid actions,
self-administration, and disruption of the sleep-wake cycle. Interruption of the light-dark cycle in rats that
increases oral morphine intake is associated with a decreased plasma concentration of melatonin. This
finding, combined with observations of diminished morphine-induced conditioned-place preference after
administration of exogenous melatonin, indicate that melatonin agonists may be useful as treatments to
prevent opioid use in humans.
 Recently, we found that pretreatment with the serotonin-2C receptor (5-HT2CR) agonist lorcaserin
increases the positive subjective effects of cocaine, suggesting a role for antagonists of this subtype.
Agomelatine but not ramelteon acts as an antagonist at the 5-HT2CR. This property, as well as melatonin
agonist activity, may decrease the reinforcing effects of opioids. Antidepressant effects of agomelatine may
also be beneficial in patients with substance abuse disorders.
 A preliminary open-label study noted decreased craving in patients with substance abuse disorders
treated with agomelatine. To initiate evaluation as potential treatments for opioid-use disorder, this project will
assess the effects of melatonin agonists with or without compounds that modify the 5-HT2CR using a rat model
of opioid-reinforced behavior.
Specific Aims:
1. Measure Effects of Ramelteon on Sleep, Tolerance-Dependence, and Morphine Self-Administration;
2. Evaluate Agomelatine, A Combined Melatonin Agonist and 5-HT2CR Antagonist; and
3. Assess Combined Effects of Ramelteon and Lorcaserin, a 5-HT2CR Agonist.
Methods Outbred Wistar rats will be maintained on a reversed light-dark cycle, with food- and morphine- self-
administration sessions conducted during darkness in the daytime. Rats will be allowed to establish opioid
dependence by self-administration of morphine. The duration and continuity of sleep and awake behaviors will
be recorded noninvasively each day when rats are returned to home cages. As morphine is withdrawn during
a one-week extinction period, m...

## Key facts

- **NIH application ID:** 9784448
- **Project number:** 1I01BX004748-01
- **Recipient organization:** KANSAS CITY VA MEDICAL CENTER
- **Principal Investigator:** KENNETH W. GRASING
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2019-10-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9784448

## Citation

> US National Institutes of Health, RePORTER application 9784448, Translating Melatonin- and Serotonin-2C Interactions into Improved Treatments for Pain and Opioid-Use Disorders (1I01BX004748-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9784448. Licensed CC0.

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