# Mechanisms of cannabinoid tolerance

> **NIH NIH R01** · MARSHALL UNIVERSITY · 2021 · $14,192

## Abstract

Project Summary/Abstract
This study will investigate the mechanisms of cannabinoid tolerance. This objective will be achieved by
determining whether cannabinoid tolerance is mediated through agonist-specific mechanisms using a
model of chemotherapy-induced neuropathic pain. Our approach will examine tolerance to the anti-
allodynic and antinociceptive effects of ∆9-THC, CP55,940, and WIN55,212-2, three cannabinoid
agonists with distinct signaling and chemical features. Tolerance to ∆9-THC antinociception in the tail-
flick test was eliminated by pre-treatment of S426A/S430A mutants with SP600125, a selective c-Jun
N-terminal kinase (JNK) inhibitor suggesting that JNK (SP600125 inhibitor) and GRK/βarrestin2
(S426/S430A mutation) signaling mechanisms coordinate to mediate tolerance to the antinociceptive
effect of ∆9-THC. The first objective of this study is to, fully and systematically, test the hypothesis that
cannabinoid tolerance is mediated through agonist-specific mechanisms. The second objective is to
test the hypothesis that JNK-mediated tolerance for ∆9-THC requires the presence of β−arrestin2. The
third objective is to test the hypothesis that β−arrestin2 and JNKs can form protein-protein interactions
in vivo. The fourth objective is to test the hypothesis that JNKs can directly phosphorylate CB1 when
activated by ∆9-THC using a technologically innovative chemical-genetic approach. The first three
hypotheses will be tested in a clinically relevant model of chemotherapy (cisplatin)-induced model of
neuropathic pain. The last hypothesis is equally innovative and will provide important information
regarding the molecular mechanism of action that is responsible for JNK-mediated ∆9-THC tolerance.
The overarching goal of this project is to gain a better understanding of the agonist-specific mechanisms
responsible for cannabinoid tolerance that will facilitate the development of long lasting, highly
efficacious, and personalized pain therapies.

## Key facts

- **NIH application ID:** 10399779
- **Project number:** 3R01DA044999-03S1
- **Recipient organization:** MARSHALL UNIVERSITY
- **Principal Investigator:** Josee Guindon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $14,192
- **Award type:** 3
- **Project period:** 2021-06-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10399779

## Citation

> US National Institutes of Health, RePORTER application 10399779, Mechanisms of cannabinoid tolerance (3R01DA044999-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10399779. Licensed CC0.

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