Positive allosteric modulation of the cannabinoid type-1 receptor (CB1R) in periaqueductal gray (PAG) antagonizes anti-n
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ORIGINAL INVESTIGATION
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periaqueductal gray (PAG) antagonizes anti-nociceptive and cellular effects of a mu-opioid receptor agonist in morphine-withdrawn rats Udita Datta 1,2 & Leslie K. Kelley 1 & Jason W. Middleton 3,4,5 & Nicholas W. Gilpin 1,4,5,6 Received: 13 July 2020 / Accepted: 20 August 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
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 antinociceptive 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 antihyperalgesic 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 When co-administered into the PAG, GAT211 antagonized the anti-nociceptive effects of DAMGO in morphine-withdrawn rats.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. Keywords Morphine . Opioids . Opiates . Pain . Hyperalgesia . PAG . Dose-response . Positive allosteric modulators
Introduction * Nicholas W. Gilpin [email protected] 1
Department of Physiology, Louisiana State University Health Science Center, Room 7205 1901 Perdido Street, New Orleans, LA 70112, USA
2
The Jackson Laboratory, Bar Harbor, ME 04609, USA
3
Department of Cell Biology & Anatomy, Louisiana State University Health Science Center, New Orleans, LA 70112, USA
4
Neuroscience Center of Excellence, Louisiana State University Health Science Center, New Orleans, LA 70112, USA
5
Alcohol & Drug Abuse Center of Excellence, Louisiana State University Health Science Center, New Or
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