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periaqueductal gray (PAG) antagonizes anti-nociceptive and cellular effects of a mu-opioid receptor agonist in morphine-withdrawn rats.
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periaqueductal gray (PAG) antagonizes anti-nociceptive and cellular effects of a mu-opioid receptor agonist in morphine-withdrawn rats.
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DOI：
10.1007/s00213-020-05650-5
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发表时间：
2020-12
影响因子：
3.4
通讯作者：
Gilpin NW
中科院分区：
文献类型：
--
作者：
Datta U;Kelley LK;Middleton JW;Gilpin NW
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 When co-administered into the PAG, GAT211 antagonized the anti-nociceptive effects of DAMGO in morphine-withdrawn rats.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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影响因子：
7.4
作者：
Morgan, MM;Clayton, CC;Boyer-Quick, JS
通讯作者：
Boyer-Quick, JS
DOI：
10.1046/j.1440-1681.2000.03291.x
发表时间：
2000-07-01
影响因子：
2.9
作者：
Christie, MJ;Connor, M;Bagley, EE
通讯作者：
Bagley, EE
影响因子：
5
作者：
Cox, Melinda L.;Haller, Victoria L.;Welch, Sandra P.
通讯作者：
Welch, Sandra P.
影响因子：
7.6
作者：
Ignatowska-Jankowska, Bogna M.;Baillie, Gemma L.;Ross, Ruth A.
通讯作者：
Ross, Ruth A.
影响因子：
16.2
作者：
Bagley, EE;Gerke, MB;Christie, MJ
通讯作者：
Christie, MJ