Effects of a Peripherally Restricted Hybrid Inhibitor of CB1 Receptors and iNOS on Alcohol Drinking Behavior and Alcohol-Induced Endotoxemia.
Molecules
; 26(16)2021 Aug 22.
Article
in English
| MEDLINE | ID: covidwho-1376916
ABSTRACT
Alcohol consumption is associated with gut dysbiosis, increased intestinal permeability, endotoxemia, and a cascade that leads to persistent systemic inflammation, alcoholic liver disease, and other ailments. Craving for alcohol and its consequences depends, among other things, on the endocannabinoid system. We have analyzed the relative role of central vs. peripheral cannabinoid CB1 receptors (CB1R) using a "two-bottle" as well as a "drinking in the dark" paradigm in mice. The globally acting CB1R antagonist rimonabant and the non-brain penetrant CB1R antagonist JD5037 inhibited voluntary alcohol intake upon systemic but not upon intracerebroventricular administration in doses that elicited anxiogenic-like behavior and blocked CB1R-induced hypothermia and catalepsy. The peripherally restricted hybrid CB1R antagonist/iNOS inhibitor S-MRI-1867 was also effective in reducing alcohol consumption after oral gavage, while its R enantiomer (CB1R inactive/iNOS inhibitor) was not. The two MRI-1867 enantiomers were equally effective in inhibiting an alcohol-induced increase in portal blood endotoxin concentration that was caused by increased gut permeability. We conclude that (i) activation of peripheral CB1R plays a dominant role in promoting alcohol intake and (ii) the iNOS inhibitory function of MRI-1867 helps in mitigating the alcohol-induced increase in endotoxemia.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Alcohol Drinking
/
Endotoxemia
/
Receptor, Cannabinoid, CB1
/
Ethanol
/
Nitric Oxide Synthase Type II
/
Cannabinoid Receptor Antagonists
Type of study:
Experimental Studies
Topics:
Long Covid
Limits:
Animals
Language:
English
Journal subject:
Biology
Year:
2021
Document Type:
Article
Affiliation country:
Molecules26165089
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