BACKGROUND AND PURPOSE:

To understand how anandamide transport inhibition impacts the regulation of nausea and vomiting and the receptor level mechanism of action involved. In light of recent characterization of an anandamide transporter, FAAH-1-like anandamide transporter (FLAT), to provide behavioral support for anandamide cellular reuptake as a facilitated transport process.

EXPERIMENTAL APPROACH:

The systemic administration of the anandamide transport inhibitor ARN272 was used to evaluate the prevention of LiCl-induced nausea-induced behaviour (conditioned gaping) in rats, and LiCl-induced emesis in shrews (Suncus murinus). The mechanism of how prolonging anandamide availability acts to regulate nausea in rats was explored by the antagonism of CB₁ receptors with the systemic co-administration of SR141716.

KEY RESULTS:

The systemic administration of ARN272 produced a dose-dependent suppression of nausea-induced conditioned gaping in rats, and produced a dose-dependent reduction of vomiting in shrews. The systemic co-administration of SR141716 with ARN272 (at 3.0 mg.kg^-1 ) in rats produced a complete reversal of ARN272-suppressed gaping at 1.0 mg.kg^-1 . SR141716 alone did not differ from VEH.

CONCLUSIONS AND IMPLICATIONS:

These results suggest that anandamide transport inhibition by the compound ARN272 tonically activates CB₁ receptors and as such produces a type of indirect agonism to regulate toxin-induced nausea and vomiting. The results also provide behavioral evidence in support of a facilitated transport mechanism used in the cellular reuptake of anandamide.
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PMID:

 

23991698

 

[PubMed – as supplied by publisher]