Pubdate: October 26, 1997 Source: Los Angeles Times Contact: 2132374712 MarijuanaLike Drugs May Be Effective Painkillers Pain relief may be provided by marijuanalike drugs that exert their influence on brain cells in the same way as the active component of the illegal weed, according to researchers from the University of California San Francisco. Ian Meng, PhD, and Barton Manning, PhD, both postdoctoral fellows, and Howard Fields, MD, PhD, a professor of neurology with the Keck Center for Integrative Neurosciences at UCSF, report that a synthetic marijuanalike drug called WIN 55212 enhances the brain's ability to suppress pain in rats, and probably in humans as well. WIN 55212 dulls pain by acting on the same painsuppressing nerve circuits as morphine and other opioid drugs, the most powerful painkillers known, the researchers say, and such drugs may one day be used in combination with opioids or other painkillers to provide better treatment for certain kinds of pain. Meng discussed the findings today at the Society for Neuroscience annual meeting in New Orleans, during a press conference. Researchers from several universities briefed reporters on studies of the painkilling properties of cannabinoids. Cannabinoids are a class of chemicals that includes tetrahydrocannabinol (THC), the component of marijuana responsible for the "high" sought by recreational users. The brain circuits affected include a key paincontrolling center called the rostral ventromedial medulla. Fields has studied the transmission of pain signals through this network for more than 15 years, identifying many key cellular mechanisms of pain suppression by investigating the actions of opioid drugs on this circuitry. Now, in studies conducted on rats, Meng has determined that cannabinoids and opioids produce similar changes within cells in the rostral ventromedial medulla. Meng also monitored pain suppression by measuring how long it took the rodents to remove their tails from an uncomfortable heat source. He found that drugs which block the painkilling effects of morphine do not eliminate the pain relief provided by WIN 55212. Furthermore, cannabinoidblocking chemicals do not reduce the effectiveness of morphine. "The results indicate that the two classes of pain relievers act through different biochemical mechanisms, even though they affect the electrical transmission of pain impulses in the cells in the same way," according to Meng. Just as the study of morphine's effects enabled Fields and other researchers to pioneer explorations of the rostral ventral medulla, the study of cannabinoids will enable scientists to gain new insights into the brain's mechanisms for suppressing or enhancing pain, Meng says. Despite their unrivaled painkilling potency, opioids can have significant side effects. These include the development of drug tolerance, whereby a patient requires everhigher doses to experience pain relief, and drug dependence, which causes a patient to become temporarily sick when opioid treatment is withdrawn. Other side effects may include confusion, nausea and constipation. The cannabinoid THC, in addition to enhancing mood in some users, is believed to reduce nausea, which may offer a significant advantage over morphine. However it also impairs mental functioning in a variety of ways. While it may not be possible to eliminate the side effects of opioids or cannabinoids used to treat pain, combining them may enhance pain relief, permitting the use of lower doses of each, and thereby alleviating the side effects, Meng suggests. In recent years scientists have identified the natural cannabinoid receptor to which THC attaches, as well as naturally occurring cannabinoids, such as anandamide, that act on this cannabinoid receptor. These discoveries and the development of synthetic cannabinoids that act more preferentially on the receptor, such as WIN 55212, should now lead to more rapid advances in understanding the function of cannabinoids in the brain, according to Meng and Fields. It is not clear why natural opioids, called endorphins, and their cannabinoid counterparts should act on many of the same nerve circuits. However, Fields speculates that the rostral ventromedial medulla nerve cells arose early in animal evolution, and may have properties similar to the primitive endocrine system. The endocrine system releases hormones that promote the survival of the animal in specific circumstances. The hormone acts upon a certain group of nerve cells that generate behavior appropriate to the situation, a fight or a flight in response to danger, for instance. In the same way, Fields suggests, natural brain cannabinoids might activate specific ensembles of nerve cells that produce behavior appropriate to particular situations. Suppression of pain through the rostral ventromedial medulla in response to cannabinoids may be one aspect of an overall behavior, such as feeding when hungry, he proposes. Even though endorphins suppress pain by acting on the same nerve cells within the brain, they may be released to perform their painkilling duties under different circumstances, such as during a freezing response to fear, Fields suggests. CONTACT: University of California, San Francisco Jeffrey Norris, 415/4762557 Copyright Los Angeles Times