# Endocannabinoid modulation of pain-depressed behavior

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2020 · $490,537

## Abstract

Treatment of severe pain is a significant clinical challenge, and use of traditional
analgesics is limited by side effects. One alternative strategy targets cannabinoid
receptors (CBRs) indirectly by inhibiting the enzyme monoacylglycerol lipase (MAGL),
which degrades the endogenous cannabinoid 2-arachidonoyl glycerol (2-AG). We
propose that MAGL inhibitors have the advantage of producing anatomically and
temporally precise increases in 2-AG release and CBR activation targeted to neural
circuits activated by pain. More specifically, this renewal application proposes to
investigate expression and mechanisms of analgesic effects produced by acute and
chronic delivery of MAGL inhibitors in novel preclinical procedures developed and
validated during the initial funding period to assess pain-depressed behaviors that model
clinically relevant manifestations of pain. The overarching hypothesis is that MAGL
inhibition will safely and effectively ease clinically relevant signs of pain-related
behavioral depression via 2-AG-mediated activation of CB1Rs that buffer activity in CNS
pain circuits. Aim 1 will compare the effects of MAGL inhibitors, direct CBR agonists,
and a systematic series of control drugs in complementary assays of pain-stimulated
and pain-depressed behavior. We hypothesize that MAGL inhibitors will produce
analgesia in all assays with minimal side effects, and preliminary data support this
hypothesis. Aim 2 will test the hypothesis that MAGL inhibitors alleviate pain-related
depression of behavior by CBR-mediated alleviation of pain-related depression of
mesolimbic dopamine circuits. We propose to localize markers of neuronal activity and
measure eCB levels in candidate regions for modulating pain-depressed behavior.
Additionally, we propose to examine effectiveness of MAGL inhibitors to relieve pain-
related depression of mesolimbic dopamine release assessed by in vivo microdialysis,
and of brain site-targeted MAGL inhibitor injections to alleviate pain-depressed behavior.
Aim 3 will assess the effects of repeatedly administered MAGL inhibitors on both
behavior and CB1R regulation in a novel model of chronic episodic pain. We hypothesize
that MAGL inhibition will produce sustained relief of pain-depressed behavior without
significant CB1R desensitization and/or downregulation in brain areas that mediate relief
of pain-depressed behavior. Successful completion of the proposed studies will inform
further consideration of MAGL inhibitors as viable options for pain treatment.

## Key facts

- **NIH application ID:** 9949684
- **Project number:** 5R01DA030404-09
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Sidney S Negus
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $490,537
- **Award type:** 5
- **Project period:** 2011-09-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9949684

## Citation

> US National Institutes of Health, RePORTER application 9949684, Endocannabinoid modulation of pain-depressed behavior (5R01DA030404-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9949684. Licensed CC0.

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