Positive allosteric modulation of the cannabinoid type-1 receptor (CB1R) in periaqueductal gray (PAG) antagonizes anti-nociceptive and cellular effects of a mu-opioid receptor agonist in morphine-withdrawn rats.

Document Type

Article

Publication Date

12-1-2020

Publication Title

Psychopharmacology

Keywords

JMG, Allosteric Regulation, Analgesics, Opioid, Animals, Cannabinoid Receptor Agonists, Enkephalin, Ala(2)-MePhe(4)-Gly(5)-, Hyperalgesia, Male, Microinjections, Morphine, Nociception, Periaqueductal Gray, Rats, Rats, Wistar, Receptor, Cannabinoid, CB1, Receptors, Opioid, mu, Substance Withdrawal Syndrome

JAX Source

Psychopharmacology (Berl) . 2020 Dec;237(12):3729-3739.

Volume

237

Issue

12

First Page

3729

Last Page

3739

ISSN

1432-2072

PMID

32857187

DOI

10.1007/s00213-020-05650-5

Grant

This work was supported in part by Merit Review Award #I01 BX003451 from the United States (U.S.) Department of Veterans Affairs, Biomedical Laboratory Research and Development Service. This work was also supported by NIH grant AA023305 (NWG) and an internal pilot grant from the LSUHSC Alcohol & Drug Abuse Center of Excellence (JWM).

Abstract

Opioid drugs are a first-line treatment for severe acute pain and other chronic pain conditions, but long-term opioid drug use produces opioid-induced hyperalgesia (OIH). Co-administration of cannabinoids with opioid receptor agonists produce anti-nociceptive synergy, but cannabinoid receptor agonists may also produce undesirable side effects. Therefore, positive allosteric modulators (PAM) of cannabinoid type-1 receptors (CB1R) may provide an option reducing pain and/or enhancing the anti-hyperalgesic effects of opioids without the side effects, tolerance, and dependence observed with the use of ligands that target the orthosteric binding sites. This study tested GAT211, a PAM of cannabinoid type-1 receptors (CB1R), for its ability to enhance the anti-hyperalgesic effects of the mu-opioid receptor (MOR) agonist DAMGO in rats treated chronically with morphine (or saline) and tested during withdrawal. We tested the effects of intra-periaqueductal gray (PAG) injections of (1) DAMGO, (2) GAT211, or (3) DAMGO + GAT211 on thermal nociception in chronic morphine-treated rats that were hyperalgesic and also in saline-treated control rats. We used slice electrophysiology to test the effects of DAMGO/GAT211 bath application on synaptic transmission in the vlPAG. Intra-PAG DAMGO infusions dose-dependently reversed chronic morphine-induced hyperalgesia, but intra-PAG GAT211 did not alter nociception at the doses we tested. When co-administered into the PAG, GAT211 antagonized the anti-nociceptive effects of DAMGO in morphine-withdrawn rats. DAMGO suppressed synaptic inhibition in the vlPAG of brain slices taken from saline- and morphine-treated rats, and GAT211 attenuated DAMGO-induced suppression of synaptic inhibition in vlPAG neurons via actions at CB1R. These findings show that positive allosteric modulation of CB1R antagonizes the behavioral and cellular effects of a MOR agonist in the PAG of rats.

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