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Pain

Description
Pain is caused in the simplest case by something dangerous - heat from the stove, the cut of a knife, electricity from an outlet, an object colliding with your toe - that damages or threatens to damage tissue in your body. Pain receptors, called nociceptors, send signals to your brain via your spinal column telling you of the danger, so you can take measures to protect yourself from further injury. This type of pain, called nociceptive pain, is the most common. Nociceptive pain can last for months or years when damaged tissues cannot heal, and chronic inflammation may be involved. Another type of pain is caused by injured nerves, or other changes in the nervous system, and is called neuropathic pain. The disturbed nervous system sends pain signals to the brain even when there is no other ongoing tissue damage. Neuropathic pain is often experienced as tingling, aching, or burning and can last for months or years. Some patients have chronic pain, and doctors cannot pinpoint the source. Often, it is best to refer to this pain as idiopathic - which means that the cause is unknown. Pain can be treated through the use of drug therapies, rehabilitation therapies, psychological therapies, anesthetic therapies, neurostimulatory therapies, surgical approaches, and alternative or complementary approaches.

Who is at Risk?
The elderly are more likely to experience pain than the general population and are often undertreated for pain due to myths about their pain sensitivity, pain tolerance, and ability to benefit from opioid drugs.

Source: Continuum Health Partners, Inc.

Turning off Pain’s Pathways
Benjamin Cravatt, Ph.D., a professor and Searle Scholar at the Skaggs Institute for Chemical Biology and the Department of Cell Biology and Director of the Helen L. Dorris Child and Adolescent Neuro-Psychiatric Disorder Institute at TSRI, has been rapidly attracting the attention of the scientific community. He recently won this year"s Eli Lilly Award in Biological Chemistry, administered by the American Chemical Society, for his contributions to biochemistry research.

Cravatt has been studying how fatty acid amines that are found in neural tissue and fluids can reduce sensitivity to pain. He and his researchers have been testing mice to see if they are less sensitive to pain in response to changing amide levels. On the molecular level, Cravatt's lab is the first to actually manipulate the entire fatty acid communications system. During the course of his investigations, Cravatt came across fatty acid amide hydrolase (FAAH), an amino acid membrane-bound enzyme that is a target for pain therapy not only because it breaks down the molecules that provide the pain relief but also because it turns out that FAAH seems to be the only enzyme responsible for doing so.

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Pain and Peptides
TSRI Professor Tamas Bartfai, Ph.D., Director of the Harold L. Dorris Neurological Research Center, is interested in the neuropeptide galanin. This chemical exists specifically in hippocampus neurons and is released into the gaps, or synapses, between two neurons during the signaling from one neuron to another that takes place during cognitive processes.

Galanin also controls the pain threshold at the spinal cord level through the same neuronal action in the spinal cord that morphine uses - hyperpolarizing primary sensory neurons. Transgenic models with no galanin receptors have different pain thresholds. One possible application for this is to develop a class of galanin receptor agonists - non-opiate pain relievers that could be taken with morphine, for instance, to lower required doses of morphine.

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Cool-temperature-sensing Protein Found by TSRI Investigators
TSRI Assistant Professor Ardem Patapoutian, Ph.D. has made breakthrough discoveries that "help explain why spicy food feels hot and breath mints give the mouth a chill." Patapoutian has identified and isolated a protein, called TRPM8, that mediates the body's ability to sense cold and menthol through the skin. TRPM8 is the first cold-sensing molecule that has ever been identified and may be an important basic target for pain-modulating drugs. While everybody knows we feel cold, it was not understood at the molecular level. The existence of specialized cold-neurons had been known for years, as had the existence of similar heat-sensing neurons. The TSRI group identified and cloned an ion channel, TRPM8, which is the first-known signaling molecule that helps the body sense cold temperatures. The channel becomes activated below 25 degrees Celsius and opens, allowing an influx of calcium ions into the axon, an electrical signal that alerts the neuron, which relays the message to the brain.

Interestingly, the channels also respond to menthol, the "cooling" flavoring and balm additive. The use of mentholated rubs for pain relief would suggest that the TRPM8 ion channels play a role in pain sensing as well. Patapoutian also identified and cloned the first-known gene that makes skin cells able to sense warm temperatures by making a protein, called TRPV3, that opens when it senses a temperature above a certain level and allows ions to pass through and cause an electrical potential that signals the brain. This protein may be important for drugs because, like other TRP channels, it may be involved in inflammation and pain-mediation.

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THC, The Brain, And Pain
Marijuana contains as a principle active ingredient the cannabinoid tetrahydrocannabinol (THC), which binds to the same receptors as the body's natural endogenous cannabinoids. This fact has made marijuana the subject of heated debate in the last decade because THC is able to mimic the action of natural cannabinoids that the body produces in signaling cascades in response to a peripheral pain stimulus. THC binds to cannabinoid receptors called "CB1" on cells of the spinal cord and pain-modulating centers of the brain to decrease sensitivity to pain. Patients with multiple sclerosis, cancer, AIDS, and a number of other conditions have sought marijuana for years to treat their various symptoms. TSRI Associate Professor Paul Schweitzer, Ph.D., studies what happens at the cellular level when THC hits the brain.

When you feel pain, you release natural endocannabinoids which provide some natural pain relief. For example, the body releases an endogenous cannabinoid called anandamide, a name derived from the Sanskrit word meaning "internal bliss." Recently, Schweitzer characterized another endogenous cannabinoid found in the brain. This new cannabinoid, called 2-arachidonyglycerol, turned out to be present in much larger amounts than anandamide in the brain. When the body senses pain, these substances bind to CB1 and nullify pain by blocking the signaling. However, this effect is weak and short-lived as other molecules metabolize the endogenous cannabinoids. These compounds have a half-life of only a few minutes in vivo. If the right chemicals could be made, they might be developed into drugs for a number of clinical conditions - from appetite modulation to safer and more effective painkillers. The challenge for scientists is to use the cannabinoid system to produce effective, long-lasting relief from pain or viable appetite modulation without the deleterious side effects of marijuana use.

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Scripps Research Scientists Provide New Understanding of Chronic Pain -- Findings Suggest New Target for Drug Development
Millions of people worldwide suffer from a type of chronic pain called neuropathic pain, which is triggered by nerve damage. Precisely how this pain persists has been a mystery, and current treatments are largely ineffective. But a team led by scientists from The Scripps Research Institute, including Gary Siuzdak, Ph.D., using a new approach known as metabolomics, has now discovered a major clue: dimethylsphingosine (DMS), a small-molecule byproduct of cellular membranes in the nervous system. In their new study, the scientists found that DMS is produced at abnormally high levels in the spinal cords of rats with neuropathic pain and appears to cause pain when injected. The findings suggest inhibiting this molecule may be a fruitful target for drug development.

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