Abstract | BACKGROUND: Activation of cannabinoid CB1 receptors suppresses pathological pain but also produces unwanted central side effects. We hypothesized that a positive allosteric modulator of CB1 signaling would suppress inflammatory and neuropathic pain without producing cannabimimetic effects or physical dependence. We also asked whether a CB1 positive allosteric modulator would synergize with inhibitors of endocannabinoid deactivation and/or an orthosteric cannabinoid agonist. METHODS:
GAT211, a novel CB1 positive allosteric modulator, was evaluated for antinociceptive efficacy and tolerance in models of neuropathic and/or inflammatory pain. Cardinal signs of direct CB1-receptor activation were evaluated together with the propensity to induce reward or aversion and physical dependence. Comparisons were made with inhibitors of endocannabinoid deactivation ( JZL184, URB597) or an orthosteric cannabinoid agonist (WIN55,212-2). All studies used 4 to 11 subjects per group. RESULTS: CONCLUSIONS: Positive allosteric modulation of CB1-receptor signaling shows promise as a safe and effective analgesic strategy that lacks tolerance, dependence, and abuse liability.
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Authors | Richard A Slivicki, Zhili Xu, Pushkar M Kulkarni, Roger G Pertwee, Ken Mackie, Ganesh A Thakur, Andrea G Hohmann |
Journal | Biological psychiatry
(Biol Psychiatry)
Vol. 84
Issue 10
Pg. 722-733
(11 15 2018)
ISSN: 1873-2402 [Electronic] United States |
PMID | 28823711
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved. |
Chemical References |
- 3-(2-nitro-1-phenylethyl)-2-phenyl-1H-indole
- Benzamides
- Benzodioxoles
- Benzoxazines
- Cannabinoid Receptor Agonists
- Carbamates
- Indoles
- JZL 184
- Morpholines
- Naphthalenes
- Piperidines
- Receptor, Cannabinoid, CB1
- cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester
- (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
- Paclitaxel
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Topics |
- Animals
- Benzamides
(pharmacology)
- Benzodioxoles
(pharmacology)
- Benzoxazines
(pharmacology)
- Cannabinoid Receptor Agonists
(pharmacology)
- Carbamates
(pharmacology)
- Cell Line, Tumor
- Disease Models, Animal
- Humans
- Hyperalgesia
(chemically induced, drug therapy)
- Indoles
(pharmacology)
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Morpholines
(pharmacology)
- Naphthalenes
(pharmacology)
- Neuralgia
(etiology)
- Paclitaxel
- Piperidines
(pharmacology)
- Receptor, Cannabinoid, CB1
(agonists, antagonists & inhibitors, metabolism)
- Reward
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