Daniele Piomelli, professor of pharmacology and director of the Center for Drug Discovery in the UCI School of Medicine, and colleagues have found that marijuana-like chemicals called endocannabinoids play a key role in stress-induced analgesia -- the body's way of initially blocking pain after an injury during periods of intense stress. In addition, the researchers have developed a novel inhibitor molecule that boosts the analgesic effect of the specific cannabinoid compound most directly related to pain relief.
Study results appear in the June 23 issue of the journal Nature.
"This study shows for the first time that natural marijuana-like chemicals in the brain have a link to pain suppression," Piomelli said. "Aside from identifying an important function of these compounds, it provides a template for a new class of pain medications that can possibly replace others shown to have acute side effects."
Scientists have long known that stress gives injured athletes or even gunshot victims a period of time in which the body's pain reaction is delayed, an effect called stress-induced analgesia. Researchers along the way have found two kinds of stress-induced analgesia mechanisms, opioid and non-opioid, and this study offers the first evidence that the non-opioid form is produced by cannabinoid compounds.
Piomelli and study co-author, Andrea Hohmann, a neuroscientist at the University of Georgia, found one specific cannabinoid compound, 2-AG, provided profound and immediate response to the body's pain reaction during stress. The researchers found that when blocking 2-AG response in test rats, they could only detect the opioid form of stress-inducted analgesia in response to pain stimuli.
Further, when rats used in study were given a small molecule inhibitor developed by Piomelli and his collaborators, stress-induced analgesia increased dramatically, proving the connection between pain suppression and the release of these marijuana-like compounds.
The inhibitor works, Piomelli said, by blocking an enzyme called monoacylglycerol lipase from moderating the production of 2-AG compounds. Piomelli points to this enzyme as a target for therapeutic drug intervention to help those in pain.
"If we design chemicals that can tweak the levels of these cannabinoid compounds in the brain, we might be able to boost their normal effects," Piomelli added.
The small molecule inhibitor developed by the Piomelli group has been patented by the University of California and the universities of Urbino and Parma (Italy). The National Institute on Drug Abuse supported the study.
Other researchers involved in the study are Darren Fegley and Regina Mangieri from UCI; Philip Holmes, Jonathon Crystal, Richard Suplita, Nathan Bolton and Mark Neely from Georgia; Jocelyn Krey and Michael Walker from Brown University; Andrea Duranti, Giorgio Tarzia and Andrea Tontini from the University of Urbino; and Marco Mor from the University of Parma.
Endogenous cannabinoid compounds are distinctive because they link with protein molecule receptors on the surface of cells, called cannabinoid receptors. (The word cannabinoid comes from the Latin name for the marijuana plant, Cannibis.) For instance, the active component in marijuana, THC, is a cannabinoid, and these receptors are activated when a person smokes the drug.
The body's natural cannabinoids function to control a variety of activities, such as pain, anxiety and appetite, so they are attractive targets for drug development. Cannabinoid-based drugs are used to reduce nausea and stimulate appetite in cancer and AIDS patients, and recent tests have shown them effective in offering relief from Tourette's syndrome and multiple sclerosis symptoms.
Piomelli is considered one of world's leading researchers on the pharmacological effects of cannabinoids. He and his colleagues made the key finding that the cannabinoid compound anandamide (the Sanskrit word for "bliss") inhibits the effects of nerve cells that transmit dopamine, which is largely responsible for stimulating movement and other motor behavior in the brain. For years, scientists have linked the uncontrolled production of dopamine to schizophrenia, Tourette's syndrome (which causes severe "nervous tics") and Parkinson's disease.
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