Inhibition of Fatty Acid Amide Hydrolase (FAAH) Reduces Contextually Elicited Gaping, a Measure of Anticipatory Nausea in Rats
Bibliographic record
Abstract
Introduction: Chemotherapy-induced nausea and vomiting are among the most challenging and troubling symptoms reported in patients receiving chemotherapy. Reports have suggested the involvement of the endocannabinoid system (including FAAH inhibition) in acute and anticipatory nausea (AN), a conditional association between treatment cues such as the clinic setting and the experience of nausea. In the current study, IW-7229, a potent, indole ketoamide FAAH inhibitor, was assessed in a rat model of AN. Methods: Rats were given 4 pairings of a novel context with lithium chloride (LiCl), and then 72 hours after the final pairing, were given a test for AN. For the AN test trial, they received either (a) intragastric (ig) pretreatments of vehicle (VEH) or IW-7229 (10, 30 or 100 mg/kg), or (b) they received a pretreatment of VEH or IW-7229 (10 mg/kg, ig), followed by an additional pretreatment of either VEH or a CB1 antagonist, SR141716 (2.5 mg/kg, ip). Two hours following the pretreatment, rats were placed in the conditioning chamber for 5 minutes while their orofacial reactions were videotaped and later scored for the number of gapes. Immediately following the AN test, rats were given a 15-min locomotor activity test to assess whether the drug produced any motor impairments. Results: IW-7229 (10 or 30 mg/kg, but not 100 mg/kg) reduced contextually elicited gaping reactions by 77% and 64% relative to VEH controls, respectively. The effect of IW-7229 (10 mg/kg) on reducing contextually-elicited gaping reactions was completely blocked by administration of SR141716. These effects occurred without producing any locomotor effects at the effective doses (10 or 30 mg/kg of IW-7229); however, at 100 mg/kg, IW-7229 did reduce locomotor activity (21% reduction relative to VEH controls). Conclusion: Inhibition of FAAH, with the FAAH inhibitor IW-7229 (10 and 30 mg/kg), reduces AN in rats, and this effect appears to be CB1 receptor-mediated, likely due to elevated endogenous anandamide levels that result from FAAH inhibition. These data support the potential utility of IW-7229 in AN and, as proof of concept has not yet been demonstrated for FAAH inhibition in the clinic, provide a novel avenue to pursue in its clinical development. Disclosure - Dr. Profy, Dr. Currie, and Dr. Segal are employees of Ironwood Pharmaceuticals. Dr. Carey is an employee of Teleos Therapeutics. This research was funded by Ironwood Pharmaceuticals.
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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 | 0.000 |
| 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 | 0.000 |
| 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".