Double dissociation of monoacylglycerol lipase inhibition and CB1 antagonism in the central amygdala, basolateral amygdala, and the interoceptive insular cortex on the affective properties of acute naloxone-precipitated morphine withdrawal in rats
Open accessAbstract
Both CB1 receptor antagonism and agonism, in particular by 2-arachidonyl glycerol (2-AG), have been shown to reduce somatic symptoms of morphine withdrawal (MWD). Here we evaluated the effects of both systemic pretreatment with the monoacylglycerol lipase (MAGL) inhibitor MJN110 (which selectively elevates 2-AG) and central administration of both MJN110 and the CB1 antagonist (AM251) on the affective properties of MWD. Acute MWD induced place aversion occurs when naloxone is administered 24 h following a single exposure to a high dose of morphine. Systemic pretreatment with the MAGL inhibitor, MJN110, prevented the aversive effects of acute MWD by a CB1 receptor-dependent mechanism. Furthermore, in a double dissociation, AM251 infusions into the central amygdala, but MJN110 infusions into the basolateral amygdala, interfered with the naloxone-precipitated MWD induced place aversion. As well, MJN110, but not AM251, infusions into the interoceptive insular cortex (a region known to be activated in acute MWD) also prevented the establishment of the place aversion by a CB1 mechanism of action. These findings reveal the respective sites of action of systemically administered MJN110 and AM251 in regulating the aversive effects of MWD.
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Inhibition of monoacylglycerol lipase in the pGIC prevents the acquisition of CPA from morphine withdrawal, which was reversed by the blockade of cannabinoid-1 receptors.
“The cannabinoid system has also been implicated, with the inhibition of monoacylglycerol lipase (causing elevation of the endocannabinoid 2-arachidonyl glycerol; 2-AG) in the pGIC preventing the acquisition of CPA from morphine withdrawal, which was reversed by the blockade of cannabinoid-1 receptors”
From The Insula: A Brain Stimulation Target for the Treatment of Addiction (2019) · cites this paper as Wills et al., 2016
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- Authors
- Wills, K. L., Petrie, G. N., Millett, G., Limebeer, C. L., Rock, E. M., Niphakis, M. J., Cravatt, B. F., & Parker, L. A.
- Affiliations
- University of Guelph (CA)
- Scripps Research Institute (US)
- Corresponding author
- Parker, Linda A
- Venue
- Neuropsychopharmacology
- Published
- 2015-12-09
- Volume
- 41
- Issue
- 7
- Pages
- 1865-1873
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC4869055
- OpenAlex
- W2193535549
- Cited by
- 25
- References
- 51
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 2 · 2023: 3 · 2021: 5 · 2020: 4 · 2019: 4 · 2018: 2 · 2016: 1
- FWCI
- 0.72
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (137122)
- Canadian Institutes of Health Research (13712_2)
- Natural Sciences and Engineering Research Council of Canada (92057)
- National Institute on Drug Abuse (R01DA032933, R01DA033760, P01DA017259)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- monoacylglycerol lipase inhibition, CB1 receptor antagonism, AM251, 2-arachidonoylglycerol, morphine withdrawal, naloxone-precipitated withdrawal, place aversion, central amygdala, basolateral amygdala, endocannabinoid system, double dissociation
- MeSH terms
- Amygdala, Analysis of Variance, Animals, Arachidonic Acids, Carbamates, Cerebral Cortex, Conditioning, Operant, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Administration Routes, Glycerides, Male, Monoacylglycerol Lipases, Morphine, Naloxone, Narcotic Antagonists, Narcotics, Substance Withdrawal Syndrome, Succinimides, Rats, Sprague-Dawley, Rats, Cannabinoid Receptor Agonists, Endocannabinoids
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