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Society for Neuroscience
27 Annual Meeting
New Orleans
MARIJUANA & ANALGESIA
Press Conference: Sunday, October 26, 11:30AM
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 ******
210-567-3881
*Symposium: Functional role of Cannabinoid Receptors
Sunday, October 26, 1 PM, room C-2, Ernest N. Morial Convention Center
**Abstract 726.10
***Abstract 706.0
****Abstract 69.5
*****Abstract 703.5
******Abstract 706.8
New research shows that substances similar
to or derived from marijuana, known as cannabinoids, could benefit the more that 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 hyperaigesia, or an enhanced sensitivity to pain, which often accompanies tissue
injury and inflammation. In addition, the new research reveals similarities and
differences between cannabinoids and a group of pain killers 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
arent better at reducing pain that traditional analgesics such as opioids. "In
general, opioids had a greater analgesic effect than cannabinoids.
In other findings, the
scientists dicovered 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 opoid 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 nerve 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 anaesthetised
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 212-2, 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 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 also have 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 war often do not feel pain for along 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 on off-cell and on-cell activity in the brain," says Meng.
Other researchers studied the spinal cord and
also have discovered that cannabinoids play a crucial role in pain processing.
"Specifically we found that cannabinoids play a crucial role in pain processing.
"Specifically we found that cannabinoids depress the reactions of spinal neurons that
transmit pain messages back 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 that
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 WIN55-212-2 into the nucleus A% in rats. "Injections of less than a tenth
of a millionth of an ounce of the cannabinoid cause a profound loss of pain sensitivity,
" says Walker. This brain area appears to contribute to pain processing by using
norepinephringe- 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, "say Walker.
The findings also provides insight on the
brains natural cannabinoid anandamide, derived from the Sanskrit word meaning
"internal bliss, "according to the researchers. The marijuana-like substance was
discovered by the cannabinoid researchers William Devance 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
bodys natural pain system also can 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, chronic
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 rats hind paw with 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 10 micrograms per
kilogram or higher of the cannabinoid exhibited a dramatic decrease in the amount of time
that they spend guarding their hind paws after the capsaicin injections, say the
researchers. Pre-treatment 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 different 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, anandamide, 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 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 to isolated
skin could prevent the release of the pain-enhancing substances following a painful
stimulus, according the researchers.