The Brain's Anti-Nausea System Works Through a Specific Endocannabinoid in a Specific Brain Region
Nausea selectively increased the endocannabinoid 2-AG (not anandamide) in the brain's visceral insular cortex, and boosting 2-AG in this region reduced nausea by dampening neural activity.
Quick Facts
What This Study Found
Researchers identified the precise brain mechanism by which the endocannabinoid system suppresses nausea. During episodes of nausea, the brain region called the visceral insular cortex (VIC) showed selective increases in 2-AG, one of the two main endocannabinoids. Anandamide, the other main endocannabinoid, was not affected.
Blocking the enzyme that breaks down 2-AG (MAGL) in the VIC reduced nausea-related behavior through CB1 receptors. Blocking the enzyme that breaks down anandamide (FAAH) had no effect on nausea.
The mechanism of action was revealed by measuring neural activation: MAGL inhibition reduced the number of activated neurons (Fos-positive cells) in the VIC during nausea, showing that 2-AG suppresses nausea by reducing neural activity in this brain region.
Key Numbers
2-AG was selectively elevated in the VIC during nausea episodes. MAGL inhibition increased 2-AG and reduced nausea via CB1 receptors. FAAH inhibition did not affect anandamide or nausea. MAGL inhibition reduced Fos immunoreactivity in the VIC.
How They Did This
Rat study using conditioned gaping (a validated model of nausea behavior) induced by lithium chloride. Researchers performed local infusions of enzyme inhibitors into the visceral insular cortex, measured endocannabinoid levels during nausea using mass spectrometry, and quantified neural activation using c-Fos immunoreactivity. CB1 receptor involvement was confirmed with the antagonist AM251.
Why This Research Matters
This study precisely identifies where and how the brain's natural anti-nausea system works. Understanding that 2-AG (not anandamide) in the visceral insular cortex is the key molecule could enable development of nausea treatments that are more targeted than whole-plant cannabis, potentially with fewer side effects.
The Bigger Picture
Cannabis has been used for nausea for centuries, but this study pinpoints the exact molecular and anatomical basis: 2-AG in the visceral insular cortex. This level of precision opens the door to targeted therapeutics that could help chemotherapy patients and others with severe nausea without the full spectrum of cannabis effects.
What This Study Doesn't Tell Us
Rat nausea models may not fully capture human nausea experience. Local brain infusions are precise but do not replicate how cannabis reaches the brain in real use. The study focused on one brain region, but nausea involves a network of brain areas. The results apply to acute, toxin-induced nausea and may not extend to all causes of nausea.
Questions This Raises
- ?Would systemic MAGL inhibitors reduce nausea in humans?
- ?Does chronic cannabis use desensitize this 2-AG-based anti-nausea system, potentially explaining cannabinoid hyperemesis syndrome?
- ?Could 2-AG-targeted therapies work for chemotherapy-induced nausea?
Trust & Context
- Key Stat:
- 2-AG, not anandamide, was the specific endocannabinoid elevated during nausea in the brain's nausea-processing center.
- Evidence Grade:
- Moderate evidence from a thorough animal study combining pharmacological, biochemical, and neuroanatomical approaches to build a consistent mechanistic picture.
- Study Age:
- Published in 2016. MAGL inhibitors for nausea continue to be explored as potential therapeutics.
- Original Title:
- Endocannabinoid regulation of nausea is mediated by 2-arachidonoylglycerol (2-AG) in the rat visceral insular cortex.
- Published In:
- Neuropharmacology, 102, 92-102 (2016)
- Authors:
- Sticht, Martin A(2), Limebeer, Cheryl L(11), Rafla, Benjamin R, Abdullah, Rehab A, Poklis, Justin L, Ho, Winnie, Niphakis, Micah J, Cravatt, Benjamin F, Sharkey, Keith A, Lichtman, Aron H, Parker, Linda A
- Database ID:
- RTHC-01273
Evidence Hierarchy
Tests effects in animals (usually mice or rats), not humans.
What do these levels mean? →Frequently Asked Questions
How does the brain fight nausea naturally?
This study shows the brain releases a specific endocannabinoid called 2-AG in its nausea-processing center (visceral insular cortex) during episodes of nausea. This 2-AG activates CB1 receptors and quiets the overactive neurons causing the nausea sensation.
Why does cannabis help with nausea?
Cannabis contains THC, which activates the same CB1 receptors that the brain's natural anti-nausea molecule (2-AG) uses. This study shows the natural system specifically targets the visceral insular cortex, suggesting cannabis may work by amplifying or mimicking this built-in nausea suppression.
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Cite This Study
https://rethinkthc.com/research/RTHC-01273APA
Sticht, Martin A; Limebeer, Cheryl L; Rafla, Benjamin R; Abdullah, Rehab A; Poklis, Justin L; Ho, Winnie; Niphakis, Micah J; Cravatt, Benjamin F; Sharkey, Keith A; Lichtman, Aron H; Parker, Linda A. (2016). Endocannabinoid regulation of nausea is mediated by 2-arachidonoylglycerol (2-AG) in the rat visceral insular cortex.. Neuropharmacology, 102, 92-102. https://doi.org/10.1016/j.neuropharm.2015.10.039
MLA
Sticht, Martin A, et al. "Endocannabinoid regulation of nausea is mediated by 2-arachidonoylglycerol (2-AG) in the rat visceral insular cortex.." Neuropharmacology, 2016. https://doi.org/10.1016/j.neuropharm.2015.10.039
RethinkTHC
RethinkTHC Research Database. "Endocannabinoid regulation of nausea is mediated by 2-arachi..." RTHC-01273. Retrieved from https://rethinkthc.com/research/sticht-2016-endocannabinoid-regulation-of-nausea
Access the Original Study
Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkTHC research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.