Chili peppers and marijuana calm the gut
The active ingredients in both hot peppers and cannabis calm the gut's immune system
April 24, 2017
Science Daily/University of Connecticut
You wouldn't think chili peppers and marijuana have much in common. But when eaten, both interact with the same receptor in our stomachs, according to a paper by UConn researchers published in the April 24 issue of the journal Proceedings of the National Academy of Sciences. The research could lead to new therapies for diabetes and colitis, and opens up intriguing questions about the relationship between the immune system, the gut and the brain.
Touch a chili pepper to your mouth and you feel heat. And biochemically, you aren't wrong. The capsaicin chemical in the pepper binds to a receptor that triggers a nerve that fires off to your brain: hot! Those same receptors are found throughout the gastrointestinal tract, for reasons that have been mysterious.
Curious, UConn researchers fed capsaicin to mice, and found the mice fed with the spice had less inflammation in their guts. The researchers actually cured mice with Type 1 diabetes by feeding them chili pepper. When they looked carefully at what was happening at a molecular level, the researchers saw that the capsaicin was binding to a receptor called TRPV1, which is found on specialized cells throughout the gastrointestinal tract. When capsaicin binds to it, TRPV1 causes cells to make anandamide. Anandamide is a compound chemically akin to the cannabinoids in marijuana. It was the anandamide that caused the immune system to calm down. And the researchers found they could get the same gut-calming results by feeding the mice anandamide directly.
The brain also has receptors for anandamide. It's these receptors that react with the cannabinoids in marijuana to get people high. Scientists have long wondered why people even have receptors for cannabinoids in their brains. They don't seem to interact with vital bodily functions that way opiate receptors do, for example.
"This allows you to imagine ways the immune system and the brain might talk to each other. They share a common language," says Pramod Srivastava, Professor of Immunology and Medicine at UConn Health School of Medicine. And one word of that common language is anandamide.
Srivastava and his colleagues don't know how or why anandamide might relay messages between the immune system and the brain. But they have found out the details of how it heals the gut. The molecule reacts with both TRPV1 (to produce more anandamide) and another receptor to call in a type of macrophage, immune cells that subdue inflammation. The macrophage population and activity level increases when anandamide levels increase. The effects pervade the entire upper gut, including the esophagus, stomach and pancreas. They are still working with mice to see whether it also affects disorders in the bowels, such as colitis. And there are many other questions yet to be explored: what is the exact molecular pathway? Other receptors also react with anandamide; what do they do? How does ingesting weed affect the gut and the brain?
It's difficult to get federal license to experiment on people with marijuana, but the legalization of pot in certain states means there's a different way to see if regular ingestion of cannabinoids affects gut inflammation in humans.
"I'm hoping to work with the public health authority in Colorado to see if there has been an effect on the severity of colitis among regular users of edible weed," since pot became legal there in 2012, Srivastava says. If the epidemiological data shows a significant change, that would make a testable case that anandamide or other cannabinoids could be used as therapeutic drugs to treat certain disorders of the stomach, pancreas, intestines and colon.
It seems a little ironic that both chili peppers and marijuana could make the gut chill out. But how useful if it's true.
https://www.sciencedaily.com/releases/2017/04/170424152537.htm
Researchers discover how the brain turns chronic stress into pathological anxiety
February 13, 2017
Science Daily/Scripps Research Institute
n a new study, researchers at The Scripps Research Institute (TSRI) have described how two important molecules in the brain work together to trigger intense anxiety.
The new findings in animal models point to a novel interaction in the regulation of the brain's stress response that may underlie the pathological anxiety related to symptoms of post-traumatic stress disorder (PTSD).
"Anxiety and stress disorders affect millions of people worldwide," explained study leader Marisa Roberto, a professor at TSRI. "Understanding the mechanisms underlying these disorders is important for identifying potential new targets for therapeutic use."
The researchers focused on the endogenous cannabinoid (endocannabinoid or eCB) system, which include natural lipid signaling molecules that bind to cannabinoid receptors in the brain. Cannabinoid (type 1) receptors control stress-mediating circuits by inhibiting neurotransmitter release -- a sort of gating mechanism to keep anxiety in check.
In contrast to the stress-reducing properties of endocannabinoids, a peptide molecule called corticotropin-releasing factor (CRF) activates the stress response and promotes increased sensitivity to stress and anxiety when activated over and over again.
In the new study, published in the journal Biological Psychiatry, the researchers investigated the interaction between the stress-promoting (CRF) and stress-constraining (eCBs) mechanisms in the central nucleus of the amygdala, a critical brain region involved in mediating emotional reactions. The findings suggest that overactive CRF signaling in this region produces a wide range of effects that override the stress-reducing capabilities of a major eCB called N-arachidonoylethanolamine (anandamide), turning chronic stress into unchecked, or pathological, anxiety.
"Anxiety is something that everyone experiences on a day-to-day basis," said study first author Luis A. Natividad, a research associate in the Roberto lab. "But it is unclear what changes this otherwise natural process into something debilitating."
To answer this question, Roberto's lab teamed up with Roberto Ciccocioppo's lab at the University of Camerino, Italy, and the lab of TSRI Professor Loren ("Larry") Parsons, a leader in the fields of endocannabinoid signaling, stress and drug addiction who passed away in 2016.
The researchers studied rats that were genetically selected for higher alcohol drinking and also display an anxiety-like phenotype. These rats exhibit a mutation in a gene called Crhr1 that increases CRF (type 1) receptor signaling.
Using behavioral, neurochemical and electrophysiological approaches, the researchers found that increased CRF signaling led to elevated activity of the anandamide clearance enzyme fatty acid amide hydrolase (FAAH). Increased CRF was also associated with drops in anandamide levels in the central nucleus of the amygdala. Together, increased FAAH activity and decreased anandamide signaling reduce inhibitory control of excitatory neurotransmission in this critical region, and lower the brain's ability to regulate stress and anxiety.
The researchers concluded that long-term dysregulation of CRF-FAAH mechanisms in the amygdala keeps anandamide from doing its job. Without anandamide to balance out the system, the brain is primed to react to stress.
Follow-up experiments showed that inhibiting FAAH could blunt CRF's effects and reduce signs of anxiety in the rats.
Roberto said the next step will be to further study this rat model to better understand relationships between high anxiety and alcoholism. She added that the rat model could also be useful for studying PTSD, where high anxiety is connected to a higher risk of developing alcoholism.
"The results of our study may be useful, not only in understanding the neurobiological basis of alcoholism, anxiety and possibly PTSD, but also in developing more efficacious pharmacotherapies to treat these disorders," added Ciccocioppo.
The researchers dedicated this study to Parsons. Natividad added a note on Parson's influence on the research and on the TSRI campus:
"Larry's guidance throughout the study was critical in bringing together a cohesive story exploring the relevance of endocannabinoid signaling with downstream neural processing in a way that is unique to the field and has translational relevance to the human condition. He serves as a role model for me not only as a scientist, but also in terms of being a good colleague, mentor and friend to those around him. I feel privileged to have been part of his lab, his teachings and mentorship. He will be dearly missed."
https://www.sciencedaily.com/releases/2017/02/170213131201.htm
New way to boost potency of natural pain relief chemical in body
November 21, 2011
Science Daily/University of California - Irvine
UC Irvine and Italian researchers have discovered a new means of enhancing the effects of anandamide -- a natural, marijuana-like chemical in the body that provides pain relief.
Led by Daniele Piomelli, UCI's Louise Turner Arnold Chair in the Neurosciences, the team identified an "escort" protein in brain cells that transports anandamide to sites within the cell where enzymes break it down. They found that blocking this protein -- called FLAT -- increases anandamide's potency.
Previous work by the researchers indicates that compounds boosting anandamide's natural abilities could form the basis of pain medications that don't produce sedation, addiction or other central nervous system side effects common with existing painkillers, such as opiates.
"These findings raise hope that the analgesic properties of marijuana can be harnessed for new, safe drugs," said Piomelli, a professor of pharmacology. "Specific drug compounds we are creating that amplify the actions of natural, marijuana-like chemicals are showing great promise."
For the study, which appears in the Nov. 20 online version of Nature Neuroscience, he and his colleagues used computational methods to understand how FLAT binds with anandamide and escorts it to cell sites to be degraded by fatty acid amide hydrolase (FAAH) enzymes.
Anandamide has been dubbed "the bliss molecule" for its similarities to the active ingredient in marijuana. A neurotransmitter that's part of the body's endocannabinoid system, it's been shown in studies by Piomelli and others to play analgesic, antianxiety and antidepressant roles. It's also important in regulating food consumption. Blocking FAAH activity enhances several effects of anandamide without generating the "high" seen with marijuana.
Piomelli and his collaborators speculate that inhibiting FLAT (FAAH-like anandamide transporters) might be particularly useful in controlling certain forms of pain -- that caused by damage to the central nervous system, for example -- and curbing addiction to such drugs as nicotine and cocaine.
Researchers from UCI, Italy's University of Parma and University of Bologna, and the Italian Institute of Technology participated in the study, which was supported by grants from the U.S. National Institute on Drug Abuse, the U.S. National Institute on Alcohol Abuse & Alcoholism, and the U.S. National Institute of General Medical Sciences.
https://www.sciencedaily.com/releases/2011/11/111121142501.htm
New Class of Chemicals Found to Use Marijuana-Like System in Brain
May 4, 2000
Science Daily/University of California, Irvine
Researchers at UC Irvine's College of Medicine have developed a chemical that could form the basis of a new class of drugs to treat a number of psychiatric disorders, including schizophrenia, Parkinson's disease, autism and attention-deficit hyperactivity disorder.
The chemical, which has been tested on rats, affects brain cells that use chemicals similar to marijuana to counteract the actions of a neurotransmitter called dopamine. Dopamine has been implicated in schizophrenia, Parkinson's disease, Tourette's syndrome and many other psychiatric disorders. The researchers' findings appear in the May issue of the Journal of Neuroscience.
Daniele Piomelli, professor of pharmacology, led a team that found that a chemical called AM404 reversed the normal inactivation of a naturally occurring chemical in the brain called anandamide, which is related to marijuana's active ingredient and opposes the actions of dopamine. By reversing the inactivation of anandamide, AM404 is able to gently curb the exaggerated movements and other disorders caused by too much dopamine activity in nerve cells.
"We were excited to find this action of AM404 in the brain. It's very encouraging to see it work in a very subtle and effective way to counteract the effects of too much dopamine-induced activity," said Piomelli. "With further testing, we hope this eventually will result in new treatments that don't have the side effects of many current psychiatric drugs."
Piomelli and his colleagues found that AM404 targeted nerves that produced unusually high levels of dopamine and caused exaggerated movements andother problems in rats. Instead of directly encouraging the production of dopamine-curbing anandamide, AM404 was found to discourage the disintegration of existing anandamide. More anandamide was then available to bind to receptors on nerve cells and reduce the stimulation of nerve cells by dopamine.
If further research proves successful, the chemical could be used to treat schizophrenia, Tourette's, Parkinson's, autism and attention-deficit disorder, all of which are currently treated by drugs that attack the dopamine system in the brain.
Piomelli warns that their research on cannabinoid receptors has shown consistently that smoking marijuana may actually make these disorders worse. "Although AM404 helps to manipulate cannabinoid receptors, we think that using marijuana directly creates too severe a reaction and can create adverse reactions among people suffering from these diseases," he said.
The researchers, who have been working for several years on detailing the cannabinoid nerve cell system in the brain, are now looking at how AM404 selects the nerve cells it affects in the brain.
"AM404's selection of nerve cells may mean that treatments may not have the side effects of many current drugs, which aren't as selective about the nerve cells they impact," Piomelli said. "Once we see how the drug actually works in the brain, we'll have a better idea of what disorders it may be most effective at treating. Using brain scans and analyzing the uptake of AM404 in rats and other animals, we can have a better idea of where it's working."
Piomelli's colleagues in this study were Massimo Beltramo and Andrea Giuffrida at UCI; Fernando Rodriguez de Fonseca, Miguel A. Gorriti and Miguel Navarro at the Complutense University, Madrid, Spain, and Antonio Calignano, Gerasimos Grammatikopoulos and Antonio G. Sadile at the University of Naples, Italy.
The researchers' work was supported by a grant from the National Institute of Drug Abuse.
https://www.sciencedaily.com/releases/2000/05/000503183344.htm
Prenatal exposure to cannabis impacts sociability of male offspring only
September 11, 2018
Science Daily/eLife
Taking cannabinoids during pregnancy can cause behavioural and neuronal deficits in adult male offspring, while females remain unaffected, says new research published in eLife.
The study in rats, from the Inserm and Aix-Marseille University Mediterranean Institute of Neurobiology, France, and Roma Tre University, Italy, in collaboration with Indiana University, US, suggests that prenatal cannabinoid use can lead to less sociability and increased neuronal excitability in males only. The findings also point towards a potential pharmacological strategy to help reverse these effects in humans.
Senior author Olivier Manzoni, Inserm Research Director at the Mediterranean Institute of Neurobiology, and Director of the CannaLab at the institute, says: "As cannabinoids can cross the placenta, they may interfere with fetal endocannabinoid signaling during neurodevelopment, which is involved in regulating a variety of processes such as pregnancy, appetite, pain sensation, and mediating the pharmacological effects of cannabis. This could in turn lead to some serious long-term deficits. But despite increasing reports of cannabis consumption during pregnancy, the long-term consequences of prenatal cannabinoid exposure remain incompletely understood."
To fill this knowledge gap, the international collaborators examined how prenatal cannabinoid exposure influences the synaptic and behavioral functions of the medial prefrontal cortex -- a brain region often implicated in neuropsychiatric disorders -- in adult male and female rats.
Their results revealed that males exposed to cannabinoids while in the uterus were less sociable than normal animals, and spent less time interacting with others. Their sniffing and playing behaviors were impaired, while the number of attacks among males remained unchanged. Additionally, the researchers saw that the exposed males had a heightened excitability of pyramidal neurons in the prefrontal cortex. None of these effects were seen in females.
"The deleterious effects of prenatal exposure to cannabinoids on social behavior were specific to male offspring only," explains co-first author Anissa Bara, who was a PhD candidate in Manzoni's lab at the time the study was carried out. "But while social interaction was specifically impaired in males, locomotion, anxiety and cognition remained unaffected in both sexes, suggesting discrete and sex-specific behavioral consequences of cannabinoid exposure during adulthood."
The results also revealed that the mGlu5 gene -- an effector of endocannabinoid signaling in the prefrontal cortex -- was reduced in the exposed males' prefrontal cortex. The team discovered that amplifying mGlu5 signaling could normalise the synaptic and behavioral deficits induced by prenatal exposure to cannabinoids partly by activating the cannabinoid type 1 receptor (CB1R). Similarly, later tests also revealed that enhancing levels of anandamide (a type of endocannabinoid) in exposed males helped to restore their social deficits via CB1R.
"Altogether, these results provide compelling evidence for sex-specific effects of prenatal cannabinoid exposure," concludes co-first author Antonia Manduca, Inserm Postdoctoral Researcher at the Mediterranean Institute of Neurobiology. "The fact that increasing mGlu5 signaling and enhancing anandamide levels helped to reverse the negative effects of early exposure in rats also hints at a new pharmacological strategy that could one day be trialled in humans."
https://www.sciencedaily.com/releases/2018/09/180911132101.htm