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

Discovery of Mechanism that Processes 'THC' Type Brain Compound May Lead to New Medicines for Pain, Addiction

March 31, 2009

Science Daily/Stony Brook University Medical Center

Dale Deutsch, Ph.D., Professor of Biochemistry and Cell Biology at Stony Brook University and colleagues discovered a new molecular mechanism for the processing of endocannabinoids, brain compounds similar to THC, the active ingredient in marijuana, and essential in physiological processes such as pain, appetite, and memory.

Reported online this week in the Proceedings of the National Academy of Sciences (PNAS), the finding could pave the way for new medicines for pain, addiction, appetite control and other disorders.

Dr. Deutsch and colleagues in the Departments of Biochemistry and Cell Biology (Martin Kaczocha) and Neurobiology and Behavior (Sherrye Glaser, Ph.D.) are the first to successfully identify two known fatty acid binding proteins (FABPs) that carry the endocannabinoid anandamide (AEA), a neurotransmitter, from the cell membrane to interior of the cell where it is destroyed. This identification enabled the research team to inhibit FABPs in various laboratory experiments and thereby reduce AEA breakdown inside cells. In their study, “Identification of intracellular carriers for the endocannabinoid anandamide,” the researchers report that they decreased the breakdown of AEA in some instances by approximately 50 percent.

“Inhibiting FABPs could potentially raise the levels of AEA in the brain’s synapses,” says Dr. Deutsch. “Naturally occurring AEA levels have been shown to curb pain without the negative side effects, such as motor coordination problems, from molecules like THC. Therefore, it makes sense to target AEA for therapeutic purposes.”

He emphasizes that their groundbreaking discovery of the role of FABPs in transporting this class of neurotransmitters may prove to be a crucial step in developing novel drug targets for endocannabinoids by way of inhibiting FABPs. In support of the research, The State University of New York (SUNY) Stony Brook Office of Technology Licensing and Industry Relations (OTLIR) has filed U.S. Patent applications comprising the discovery.

The OTLIR manages all intellectual property matters for the SUNY Research Foundation. In actively marketing this unlicensed technology created by Dr. Deutsch, the Stony Brook OTLIR welcomes commercial entities interested in partnering with the University. The licensing agent for the project is Adam DeRosa of the OTLIR.

The breakdown of AEA requires two factors. First, there needs to be a mechanism for transporting AEA to the location where it is inactivated because AEA is a fatty compound and thus unable to move inside the watery cellular environment. Second, the cell must express an enzyme called FAAH, which controls the breakdown and inactivation of AEA. In the laboratory, the researchers coaxed a nonneuronal cell type (COS-7) to express FAAH. These FAAH-expressing COS-7 cells were able to break down AED efficiently, indicating that the intracellular AEA transport mechanism was already present and operation in these cells. The researchers identified these carriers as two separate FABPs.

Dr. Deutsch believes that because a transporter for the AEA class of neurotrasmitters had never been discovered until the Stony Brook findings, continued research may explain many unanswered questions about AEA. Future research may uncover more knowledge about AEA transport, as well as the entire role these neurotransmitters play in pain, inflammation, appetite control, addiction, and perhaps other physiological processes related to many human disorders.

The research was funded by the National Institute on Drug Abuse, part of the National Institutes of Health.

https://www.sciencedaily.com/releases/2009/03/090325190342.htm

Marijuana-like Brain Chemicals Work as Antidepressant

November 7, 2007

Science Daily/University of California - Irvine

American and Italian researchers have found that boosting the amounts of a marijuana-like brain transmitter called anandamide produces antidepressant effects in test rats.

Led by Daniele Piomelli, the Louise Turner Arnold Chair in Neurosciences and director of the Center for Drug Discovery at the University of California, Irvine, the researchers used a drug they created, called URB597, which blocks anandamide degradation in the brain, thereby increasing the levels of this chemical.

“These findings raise the hope that the mood-elevating properties of marijuana can be harnessed to treat depression,” Piomelli said. “Marijuana itself has shown no clinical use for depression. However, specific drugs that amplify the actions of natural marijuana-like transmitters in the brain are showing great promise.”

The researchers administered URB597 to chronically stressed rats which showed behaviors similar to those seen in depressed human patients. After five weeks of treatment, the stressed rats treated with the drug were behaving similarly to a comparison group of unstressed animals. 

URB597 works by inhibiting FAAH, an enzyme in the body that breaks down anandamide.  Dubbed “the bliss molecule” for its similarities to the active ingredient in marijuana, anandamide is a neurotransmitter that is part of the brain’s endocannabinoid system and it has been shown in studies by Piomelli and others to play analgesic, anti-anxiety and antidepressant roles. It also is involved in regulating feeding and obesity. Blocking FAAH activity boosts the effects of anandamide without producing the “high” seen with marijuana.

Piomelli and colleagues at the Universities of Urbino and Parma in Italy created URB597. A patent was issued in 2007. The European pharmaceutical company Organon holds the license to the patent and will begin clinical studies on the drug in 2008, according to Piomelli.

Marco Bortolato, Regina Mangieri, Jin Fu, Janet Kim and Oliver Arguello of UC Irvine; Andrea Duranti, Andrea Tontini and Giorgio Tarzia of the University of Urbino; and Marco Mor of the University of Parma also participated in the study. It was supported by the National Institute on Drug Abuse, the University of California Discovery Program and the National Alliance for Research on Schizophrenia and Depression.

https://www.sciencedaily.com/releases/2007/11/071105120556.htm