An endocannabinoid mechanism for stress-induced analgesia

By A. Hohmann, R. L. Suplita, Nathan M. Bolton, Mark H. Neely, D. Fegley, R. Mangieri, J. Krey, J. Walker, P. Holmes, J. Crystal and 5 more. Nature, 2005

756 citations recorded by the source corpus.

Acute stress suppresses pain by activating brain pathways that engage opioid or non-opioid mechanisms. Here we show that an opioid-independent form of this phenomenon, termed stress-induced analgesia, is mediated by the release of endogenous marijuana-like (cannabinoid) compounds in the brain. Blockade of cannabinoid CB1 receptors in the periaqueductal grey matter of the midbrain prevents non-opioid stress-induced analgesia. In this region, stress elicits the rapid formation of two endogenous cannabinoids, the lipids 2-arachidonoylglycerol (2-AG) and anandamide. A newly developed inhibitor of the 2-AG-deactivating enzyme, monoacylglycerol lipase, selectively increases 2-AG concentrations and, when injected into the periaqueductal grey matter, enhances stress-induced analgesia in a CB1-dependent manner. Inhibitors of the anandamide-deactivating enzyme fatty-acid amide hydrolase, which selectively elevate anandamide concentrations, exert similar effects. Our results indicate that the coordinated release of 2-AG and anandamide in the periaqueductal grey matter might mediate opioid-independent stress-induced analgesia. These studies also identify monoacylglycerol lipase as a previously unrecognized therapeutic target.

Subfields: Cognitive Neuroscience, Pharmacology, Toxicology

View Paper: https://www.semanticscholar.org/paper/ca6d49734baee651c35853328dd9d63dfeb196f4

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cognitive Neuroscience

1. David P. Finn
2. R. K. Butler
3. George Kunos
4. V. Di Marzo

In Pharmacology

1. V. Di Marzo
2. B. Cravatt
3. George Kunos
4. P. Pacher
5. S. Batkai
6. Jonathan Z. Long
7. David P. Finn
8. R. K. Butler

In Toxicology

1. B. Cravatt
2. Jonathan Z. Long
3. George Kunos
4. V. Di Marzo

Citations in the corpus

• Stress-induced analgesia. (2009, background): “Abbreviations: SIA, stress-induced analgesia; FCA, fear-conditioned analgesia; GABA, g-aminobutyric acid; HA, high analgesia; LA, low analgesia; fMRI, functional magnetic resonance imaging; DNIC, diffuse noxious inhibitory control; PAG, periaqueductal grey; RVM, rostroventral medulla; 5-HT, 5-hydrox”
• Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects (2008, background): “JZL184 (6) X R1 R2 Figure 1 Structures and competitive ABPP profiles of MAGL inhibitors.”
• Descending control of nociception: Specificity, recruitment and plasticity. (2009, background): “…system has a pivotal role in organizing strategies for coping with intrinsic and extrinsic stressors, and is also recognized as the central site of action of analgesic agents including opioids, cyclooxygenase inhibitors, and cannabinoids (Hohmann et al, 2005; Leith et al, 2007; Yaksh et al, 1976).”
• Neurobiological Interactions Between Stress and the Endocannabinoid System (2016, methodology): “Two separate studies have both found that footshock actually elevates, not reduces, AEA levels in the mPFC, amygdala, hippocampus, and periaqueductal gray (Hohmann et al, 2005; Morena et al, 2014b).”
• A Comprehensive Profile of Brain Enzymes that Hydrolyze the Endocannabinoid 2‐Arachidonoylglycerol (2007, background): “Endocannabinoid signaling has been found to modulate a number of physiological processes, including pain sensation [ 3 ], appetite [4], and cognitive and emotional state [5, 6].”
• The Endocannabinoid System as an Emerging Target of Pharmacotherapy (2006, result): “…gray matter, in which inhibition of endocannabinoid degradation was found to enhance stress-induced analgesia in a CB1 receptor-dependent manner (Hohmann et al., 2005; Suplita et al., 2006), confirming and extending an earlier finding that implicated CB1 receptors and endocannabinoids in…”
• Effects of cannabinoids and cannabinoid‐enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes (2011, background): “These findings indicate that these extracts might be used to inhibit chronic and inflammatory pain, because URB602, a synthetic compound with lower potency at MAGL than THCA-BDS, CBDA-BDS and CBG-BDS, was previously reported to act as an efficacious anti-hyperalgesic and anti-inflammatory compound i”