Background and Purpose
To evaluate the ability of cannabidiolic acid (CBDA) to reduce nausea and vomiting and enhance 5‐HT1A receptor activation in animal models.
Experimental Approach
We ...investigated the effect of CBDA on (i) lithium chloride (LiCl)‐induced conditioned gaping to a flavour (nausea‐induced behaviour) or a context (model of anticipatory nausea) in rats; (ii) saccharin palatability in rats; (iii) motion‐, LiCl‐ or cisplatin‐induced vomiting in house musk shrews (Suncus murinus); and (iv) rat brainstem 5‐HT1A receptor activation by 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT) and mouse whole brain CB1 receptor activation by CP55940, using 35SGTPγS‐binding assays.
Key Results
In shrews, CBDA (0.1 and/or 0.5 mg·kg−1 i.p.) reduced toxin‐ and motion‐induced vomiting, and increased the onset latency of the first motion‐induced emetic episode. In rats, CBDA (0.01 and 0.1 mg·kg−1 i.p.) suppressed LiCl‐ and context‐induced conditioned gaping, effects that were blocked by the 5‐HT1A receptor antagonist, WAY100635 (0.1 mg·kg−1 i.p.), and, at 0.01 mg·kg−1 i.p., enhanced saccharin palatability. CBDA‐induced suppression of LiCl‐induced conditioned gaping was unaffected by the CB1 receptor antagonist, SR141716A (1 mg·kg−1 i.p.). In vitro, CBDA (0.1–100 nM) increased the Emax of 8‐OH‐DPAT.
Conclusions and Implications
Compared with cannabidiol, CBDA displays significantly greater potency at inhibiting vomiting in shrews and nausea in rats, and at enhancing 5‐HT1A receptor activation, an action that accounts for its ability to attenuate conditioned gaping in rats. Consequently, CBDA shows promise as a treatment for nausea and vomiting, including anticipatory nausea for which no specific therapy is currently available.
BACKGROUND AND PURPOSE Cannabinoid CB1 receptor antagonists reduce food intake and body weight, but clinical use in humans is limited by effects on the CNS. We have evaluated a novel cannabinoid ...antagonist (AM6545) designed to have limited CNS penetration, to see if it would inhibit food intake in rodents, without aversive effects.
EXPERIMENTAL APPROACH Cannabinoid receptor binding studies, cAMP assays, brain penetration studies and gastrointestinal motility studies were carried out to assess the activity profile of AM6545. The potential for AM6545 to induce malaise in rats and the actions of AM6545 on food intake and body weight were also investigated.
KEY RESULTS AM6545 binds to CB1 receptors with a Ki of 1.7 nM and CB2 receptors with a Ki of 523 nM. AM6545 is a neutral antagonist, having no effect on cAMP levels in transfected cells and was less centrally penetrant than AM4113, a comparable CB1 receptor antagonist. AM6545 reversed the effects of WIN55212‐2 in an assay of colonic motility. In contrast to AM251, AM6545 did not produce conditioned gaping or conditioned taste avoidance in rats. In rats and mice, AM6545 dose‐dependently reduced food intake and induced a sustained reduction in body weight. The effect on food intake was maintained in rats with a complete subdiaphragmatic vagotomy. AM6545 inhibited food intake in CB1 receptor gene‐deficient mice, but not in CB1/CB2 receptor double knockout mice.
CONCLUSIONS AND IMPLICATIONS Peripherally active, cannabinoid receptor antagonists with limited brain penetration may be useful agents for the treatment of obesity and its complications.
Oleoylethanolamide (OEA) is an endogenous lipid produced in the intestine that mediates satiety by activation of peroxisome proliferator‐activated receptor alpha (PPARα). OEA inhibits gastric ...emptying and intestinal motility, but the mechanism of action remains to be determined. We investigated whether OEA inhibits intestinal motility by activation of PPARα. PPARα immunoreactivity was examined in whole mount preparations of mouse gastrointestinal (GI) tract. The effect of OEA on motility was assessed in wildtype, PPARα, cannabinoid CB1 receptor and CB2 receptor gene‐deficient mice and in a model of accelerated GI transit. In addition, the effect of OEA on motility was assessed in mice injected with the PPARα antagonist GW6471, transient receptor potential vanilloid 1 antagonist SB366791 or the glucagon‐like peptide 1 antagonist exendin‐3(9‐39) amide. PPARα immunoreactivity was present in neurons in the myenteric and submucosal plexuses throughout the GI tract. OEA inhibited upper GI transit in a dose‐dependent manner, but was devoid of an effect on whole gut transit or colonic propulsion. OEA‐induced inhibition of motility was still present in PPARα, CB1 and CB2 receptor gene‐deficient mice and in the presence of GW6471, SB366791 and exendin‐3(9‐39) amide, suggesting neither PPARα nor the cannabinoids and other likely receptors are involved in mediating the effects of OEA. OEA blocked stress‐induced accelerated upper GI transit at a dose that had no effect on physiological transit. We show that PPARα is found in the enteric nervous system, but our results suggest that PPARα is not involved in the suppression of motility by OEA.
Background and Purpose
To evaluate the ability of cannabidiolic acid (
CBDA
) to reduce nausea and vomiting and enhance 5‐
HT
1A
receptor activation in animal models.
Experimental Approach
We ...investigated the effect of
CBDA
on (i) lithium chloride (
LiCl
)‐induced conditioned gaping to a flavour (nausea‐induced behaviour) or a context (model of anticipatory nausea) in rats; (ii) saccharin palatability in rats; (iii) motion‐,
LiCl
‐ or cisplatin‐induced vomiting in house musk shrews (
S
uncus murinus
); and (iv) rat brainstem 5‐
HT
1A
receptor activation by 8‐hydroxy‐2‐(di‐
n
‐propylamino)tetralin (8‐
OH‐DPAT
) and mouse whole brain
CB
1
receptor activation by
CP
55940, using
35
S
GTP
γ
S
‐binding assays.
Key Results
In shrews,
CBDA
(0.1 and/or 0.5 mg·kg
−1
i.p.) reduced toxin‐ and motion‐induced vomiting, and increased the onset latency of the first motion‐induced emetic episode. In rats,
CBDA
(0.01 and 0.1 mg·kg
−1
i.p.) suppressed
LiCl
‐ and context‐induced conditioned gaping, effects that were blocked by the 5‐
HT
1A
receptor antagonist,
WAY
100635 (0.1 mg·kg
−1
i.p.), and, at 0.01 mg·kg
−1
i.p., enhanced saccharin palatability. C
BDA
‐induced suppression of
LiCl
‐induced conditioned gaping was unaffected by the
CB
1
receptor antagonist,
SR141716A
(1 mg·kg
−1
i.p.).
In vitro
,
CBDA
(0.1–100
nM
) increased the
E
max
of 8‐
OH‐DPAT
.
Conclusions and Implications
Compared with cannabidiol,
CBDA
displays significantly greater potency at inhibiting vomiting in shrews and nausea in rats, and at enhancing 5‐
HT
1A
receptor activation, an action that accounts for its ability to attenuate conditioned gaping in rats. Consequently,
CBDA
shows promise as a treatment for nausea and vomiting, including anticipatory nausea for which no specific therapy is currently available.
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