# Mechanisms of cannabinoid tolerance

> **NIH NIH R01** · MARSHALL UNIVERSITY · 2021 · $370,211

## 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:** 10224956
- **Project number:** 5R01DA044999-04
- **Recipient organization:** MARSHALL UNIVERSITY
- **Principal Investigator:** Josee Guindon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $370,211
- **Award type:** 5
- **Project period:** 2020-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10224956

## Citation

> US National Institutes of Health, RePORTER application 10224956, Mechanisms of cannabinoid tolerance (5R01DA044999-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10224956. Licensed CC0.

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