MARIJUANA & ANALGESIA

Press Conference: Sunday, October 26, 11:30 A.M.

Samuel Deadwyler, Wake Forest University Medical School*

910-716-8540

Jeffrey Vivian, University of Michigan Medical School **

313-647-3119

Ian Meng, University of California at San Francisco***

415-476-9624

J. Michael Walker, Brown University****

401-863-2048

Donald Simone, University of Minnesota*****

612-625-6464

Kenneth Hargreaves, University of Texas

210-567-3381

Symposium: Functional Role of Cannabinoid Receptors

Sunday, October 26, 1 p.m. Room C-2, Ernest N. Moral Convention Center

**Abstract 726.10

***Abstract 706.6

*******Abstract 69.5

Abstract 703.5

Abstract 706.8

202-462-6688

Society for Neuroscience

Syllabus (copy of whole)

New research shows that substances similar to or derived from marijuana, known as cannabinoids, could benefit more than 97 million Americans who experience some form of pain each year.

In the past, the majority of evidence suggesting that cannabinoids could crush pain without causing a loss of touch was anecdotal. Some animal studies did show that cannabinoids decreased pain sensitivity in animals, but they also induced a wide variety of additional behavioral effects, such as changes in attention, deficits in movement, and cognitive impairment. It was unclear whether the animals showed a decrease in pain sensitivity because of these other behavioral effects or if the cannabinoids directly targeted the pain system.

Now careful studies are showing that the substances have a direct affect on pain signals in the central nervous system and peripheral tissues. The cannabinoids not only act as an analgesic, but also prevent the condition hyperalgesia, or an enhanced sensitivity to pain, which often accompanies tissue injury and inflammation. In addition, the new research reveals similarities and indifferences between cannabinoids and group of painkillers that are used today called opioids or morphine-like drugs. Opioids are very effective but also cause many unwanted side effects. The most severe is physical dependence. The studies show that cannabinoids could be manipulated to form a new type of pain reliever.

In one new study scientists show that the active ingredient in marijuana, delta-9-THC, and another synthetic Cannabinoid, WIN 55212, exhibit analgesic characteristics in monkeys. In addition, the pain relief occurs through a system that is different from opioids, according to the researchers from the University of Michigan Medical School.

In the study, the researchers measured the compounds analgesic characteristics in three rhesus monkeys with a technique that involved a warm-water bath. Monkeys will keep their tails in water kept at 50 degrees Celsius for a longer time than normal if they have received drugs with analgesic properties. "As the dose of the cannabinoids or the opioids increased, the monkeys were slower to remove their tails from the warm-water bath, revealing an analgesic action for these compounds, "says Jeffrey Vivian. "It is important to note, however, that many cannabinoids produce a very rapid tolerance necessitating the use of higher doses and they aren't better at reducing pain than traditional analgesics such as opioids. " In general, opioids had a greater analgesic effect than cannabinoids.

In other findings, the scientist discovered that the administration of a drug that incapacitates the cannabinoids will block the cannabinoid effects but not the opioid effects. And a drug that solely knocks the opioids out of commission will block the opioid effects but not the cannabinoid effects. "This demonstrates the independence of the cannabinoid and opioid systems to cause pain relief, says Vivian.

Another group of researchers also found that cannabinoids and opioids relieve pain through different mechanisms. They found, however, that cannabinoids and opioids both target the same pain-modulating never cells or neurons.

"The results suggest that marijuana-like drugs may be useful as an adjuvant in combination with other therapies for treating certain types of pain," says Ian Meng of the University of California at San Francisco.

Meng and his co-workers studied anesthetized rats with electrophysiology, a technique that allowed the researchers to measure the electrical impulses, known as action potentials, of single brain cells in a region of the brain that modulates pain. They found that following administration of the synthetic cannabinoid, WIN55-122-2, the rats no longer moved their tails away from a heat source. This shows a sign of reduced pain. In addition the effect of the cannabinoid was not reversed by a drug that prevents the action out of the opioid, morphine, nor was the effect of morphine reversed by a drug that prevents the action of cannabinoids. "While this shows that the drugs reduce pain through different mechanisms, we have also shown that both cannabinoids, and opioids produce similar changes in the activity of specific neurons that help reduce pain," says Meng.

These neurons are in the rostral ventromedial medulla, a pain-modulating center of the brain. Scientists recently discovered that under certain circumstances pain signals can be modulated by certain brain areas. These pain-modulating centers can increase or decrease the amount of pain a person feels by influencing the number of pain signals that are allowed to pass through the spinal cord. "For example, people injured in ware often do not feel pain for a long time after the injury because pain-modulating centers prevent pain information from reaching parts of the brain that are important for the conscious perception of pain." Says Meng.

In the rostral ventromedial medulla region, there are two types of neurons that control pain transmission through the spinal cord. The "off cell" neurons can inhibit the pain signals passing through the spinal cord. The "On cell neurons may actually increase the amount of pain signals. Previous studies have shown that morphine increases the activity of off-cell neurons and decreases the activity of on-cell neurons. "Our study shows that cannabinoids can produce the same effect as morphine ion off-cell and on-cell activity in the brain," says Meng.

Other researchers studied the spinal cord and also have discovered cannabinoids play a crucial role in pain processing. "Specifically we found that cannabinoids depress the reactions of spinal neurons that transmit pain messages to the brain," says J. Michael Walker of Brown University. "The responses of neurons that transmit messages about non-painful stimuli, however, are unaltered."

In addition, the researchers found the cannabinoids target the brain region, nucleus A5, which is near the rostral ventromedial region and like that area, acts in the front of the pain processing loop, by sending painful messages to the spinal cord.

In the study, the scientists injected the cannabinoid WIN55212-2 into the nucleus A5 in rats. "Injections of less than a tenth of a millionth of an ounce of the cannabinoid caused a profound loss of pain sensitivity," says Walker. This brain area appears to contribute to pain processing by using norepinephrine-a brain neurotransmitter-to send messages. The messages can block the transmission of information about painful events. Past research has shown that injections of drugs that block the action of norepinephrine also inhibit the analgesic effects of cannabinoids. "Our new research isolates the particular source of norepinephrine and makes a direct link to pain pathways in the brain," says Walker.

The finding also provides insight on the brain's natural cannabinoid, anandamide, derived from the Sanskrit word meaning "internal bliss," according to researchers. The marijuana-like substance was discovered by the cannabinoid researchers William Devane and Raphael Mechoulam, in 1992. It produces its effects on the brain through the same chemical mechanism that is used by the main psychoactive constituent of the marijuana plant. "The new research provides insight into the functions of this newly discovered neuro-chemical system by demonstrating that the synthetic cannabinoids act on known pathways that function naturally to control the entry of pain messages into the spinal cord," says Walker.

The cannabinoids ability to target the body's natural pain system can also prevent the development of an enhanced sensitivity to pain, or hyperalgesia, according to a new study by researchers at the University of Minnesota. Pain and hyperalgesia often accompany tissue injury and inflammation. Severe hyperalgesia, which can be debilitating and often difficult to treat, also is associated with many chronic painful syndromes such as nerve disease, hornic inflammation and spinal cord injury. The condition can be so intense that warming the skin or gently touching the skin is perceived as painful.

In the new work, the researchers infused the cannabinoid WIN55 212-2 intravenously into the rats. Next they initiated a model of hyperalgesia by injecting the rat's hind paw with capsaicm, the pungent ingredient in hot chili peppers. The pain and hyperalgesia from capsaicin was shown to be due in part to the activation and hyperactivity of pain neurons in the spinal cord to touching or gently warming the skin," says Donald Simone. "In these studies we determined that cannabinoids would block the pain as well as the hyperactivity of spinal neurons.

Animals that received ten micrograms per kilogram or higher of the cannabinoid exhibited a dramatic decrease in the amount of time that they spent guarding their hind paws after the capsaicin injections, says the researchers. Pretreatment with the cannabinoid also decreased the amount of sensitivity observed to warmth and touch. And animals that received 100 micrograms per kilogram of the cannabinoid did not display any hyperalgesia at all. "In fact, their withdrawal responses to noxious heating were normal." Says Simone. "This demonstrates that the cannabinoid did not impair the animals' capability to withdraw from the stimulus. "

Another group studied a deficient rat model of hyperalgesia, the carrageenan model. This model of inflammation has previously been shown to be predictive of drugs which relieve pain due to arthritis. The researchers discovered that the natural cannabinoid anandamid, produced pain relief when it was injected in the skin at the site of the perceived injury. While cannabinoids can interact with receptors or receiving areas on pain sensitive cells in the spinal cord and brain to reduce pain, they also have an opportunity to initiate side effects such as disorientation, say the researchers. "These results suggest that local administration of the cannabinoid to the site of injury may be able to both prevent pain from occurring and reduce pain which has already occurred without producing side effects," says Kenneth Hargreaves of the University of Texas who conducted the research when he was at the University of Minnesota. The researchers believe side effects are limited because the cannabinoid acts locally and does not reach the spinal cord or brain.

Hargreaves found that the cannabinoid works immediately in the peripheral tissues by reducing the amount of leakiness in nearby blood vessels and preventing the flow of pain-enhancing substances. Hyperalgesia is known to occur when blood vessels become leaky and allow compounds, some of which activate pain receptors, to flow into the injured tissue. The administration of anandamide is isolated, skin could prevent the release of pain-enhancing substances following a painful stimulus, according to the researchers.

"Collectively the research shows that the cannabinoid administered at the site of injury works locally to produce analgesia with limited side effects says Hargreaves.