Selective inhibition of <scp>FAAH</scp> produces antidiarrheal and antinociceptive effect mediated by endocannabinoids and cannabinoid‐like fatty acid amides
Bibliographic record
Abstract
BACKGROUND: The endogenous cannabinoid system (ECS) plays a crucial role in multiple physiological processes in the central nervous system and in the periphery. The discovery that selective cannabinoid (CB) receptor agonists exert a potent inhibitory action on gastrointestinal (GI) motility and pain has placed the ECS in the center of attention as a possible target for the treatment of functional GI diseases. However, side effects of CB agonists prompted the search for novel therapeutic targets. Here, the effect of PF-3845, a potent and selective fatty acid amide hydrolase (FAAH) inhibitor in the GI tract was investigated. METHODS: The effect of PF-3845 on GI motility was characterized in vitro and in vivo, using mouse models that mimic physiological and pathophysiological conditions. The antinociceptive action of PF-3845 was evaluated on the basis of behavioral pain models. Endocannabinoid degradation product levels after inhibition of FAAH were quantified using HPLC-MS/MS. KEY RESULTS: PF-3845 significantly inhibited mouse colonic motility in vitro and in vivo. Selective inhibition of FAAH reversed hypermotility and reduced pain in mouse models mimicking functional GI disorders. The effects of PF-3845 were mediated by endogenous CBs and non-CB lipophilic compounds via classical (CB1) and atypical CB receptors. CONCLUSIONS & INFERENCES: These data expand our understanding of the ECS function and provide a novel framework for the development of future potential treatments of functional GI disorders.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".