NEWS

Causes of Pain Investigated at Molecular Level

Steve Benowitz

Molecular biologists, physiologists, and anesthesiologists are leading a quiet revolution in understanding an all-too-common, often-overlooked enemy that millions—including cancer patients—know too well: chronic pain.

Researchers have spent the past two decades unearthing receptors, channels, and molecules involved in different types of pain, attempting to root out biochemical mechanisms while inching ever closer to designing drugs to block them.

Even though research is promising, many contend that in practice the chronic pain problem is vastly underappreciated. "Pain can’t be seen and you can’t measure it—it’s entirely subjective," said Allan Basbaum, Ph.D., professor and chair of the Department of Anatomy at the University of California at San Francisco. He and many others see chronic pain as a disease and lament what they perceive as a lack of attention by oncologists.



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Dr. Allan Basbaum

 
Miles Day, M.D., assistant professor of pain management and anesthesiology at Texas Tech University Health Sciences Center in Lubbock, said some 85% of cancer patients will experience pain—not to mention fear and depression—at some point in their disease and treatment.



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Dr. Miles Day

 
"We as physicians have done a poor job in treating cancer pain," Day said. Approximately 85% to 90% of such pain can be effectively treated with oral medications, such as gammapentin, particularly for neuropathic pain, he added.

Most doctors aren’t trained in pain medicine, and those who are may be trained incorrectly, said medical oncologist Judith Kaur, M.D., assistant professor of medicine at the Mayo Clinic in Rochester, Minn. In some cases, doctors are afraid of using the necessary drugs for fear of unwanted side effects and addiction, although such fears have been unfounded. But she still believes the situation is beginning to turn around.



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Dr. Judith Kaur

 
"I sometimes refer to pain as a fifth vital sign," Kaur said. "We need to reinforce doctors’ responsibilities in relieving cancer pain."

And scientists are working to make the doctors’ jobs easier.

"We’re beginning to uncover the chemistry of pain at a level we never understood before," said Patrick Mantyh, Ph.D., professor of neuroscience, preventive science and psychiatry at the University of Minnesota and a research scientist at the Minneapolis VA Medical Center.

Types of Pain

Scientists have come to realize that all pain is not created equal—quite the opposite of the thinking 20 or 30 years ago, when it was assumed that inflammatory pain from tissue damage was similar to neuropathic pain, where the nerve is injured.

"We know now that each one of these chronic pains is probably produced by a different mechanism," Mantyh said. "Now we understand that there are unique biochemical changes that occur in each pain state and you can sort out the differences between inflammatory, neuropathic, and cancer pain."

Specialists classify pain more or less in two ways (not counting the broader acute and chronic varieties): nociceptive and neuropathic. Nociceptive pain results from tissue injury—a broken arm, for example, or a burned hand. Nerve damage incurs neuropathic pain, such as in diabetic neuropathy.

In pain, specialized nerve cells called nociceptors carry the chemical message to the spinal cord. Another group of neurons relays the information from the cord to the brain. A combination of improved imaging techniques and animal models have enabled scientists to see various neurochemical patterns in the spinal cord after a painful stimulus and begin to grasp how neurological processes are activated, leading to pain, said Tony Yaksh, Ph.D., a professor of anesthesiology at the University of California at San Diego Cancer Center.

Cancer pain is a hybrid, probably a varied combination of pain types, Yaksh said, and particularly complex. "Cancer is unique because it is progressive and can cause several types of pain," added neuroscientist William Willis, M.D., Ph.D., professor and chairman of anatomy and neurosciences at the University of Texas Medical Branch at Galveston. "You can have cancer pain that emphasizes one mechanism or several."

Both the cancer itself and its treatment can cause pain. A tumor can invade and short-circuit a nerve, or simply compress it, for example, much like carpal tunnel syndrome, resulting in pain. Some chemotherapeutic drugs such as vinblastine, vincristine, and taxol can damage nerves, leaving a burning sensation. A patient with a head and neck tumor may have skin ulcers, causing inflammation and tissue injury. Some cancer surgeries may destroy nerves. Radiation can wreck nerve signals.

Neurochemical Changes Abound

Continuing pain can eventually have residual effects on the central nervous system, and scientists are beginning to understand the dramatic reorganization of both local nerve and spinal cord neurochemistry that accompanies chronic pain. "It is important to recognize that the nervous system changes when there is persistent injury and pain," said Basbaum.

One type of change is called peripheral sensitization. This heightened sensitivity causes nerve cells in the pain pathway to overreact to painful and what would otherwise be nonpainful stimuli. In central sensitization, the neurochemistry of the spinal cord actually changes due to chronic pain.

At the February American Association for the Advancement of Science meeting in Washington, D.C., Basbaum described biochemical changes in sensitization occurring "downstream," away from the injury site. So-called "second messenger" systems kick in and "alter the structure, chemistry, genetics, and molecular biology of the spinal cord and the transmission system," he said.

"The spinal cord is sensitized, and the molecular biology of that change is analogous to a memory system for pain." The pain pathway expresses "unique molecules not expressed anywhere else in the body," he said.

Among those molecules are the capsaicin receptor and the tetrodotoxin resistant sodium channel. Capsaicin is well known as the "hot" substance in spicy foods. Eating spicy food activates the capsaicin receptor, which transmits a pain signal. Other scientists at UCSF and elsewhere are attempting to overstimulate the capsaicin receptor, perhaps desensitizing it, to actually diminish pain.

New Drugs, New Techniques

Such molecular targets may be key to creating new drugs to battle persistent pain. "The greatest challenge for pain research," said Basbaum, "is to develop selective drugs for the many molecular and biochemical targets we have.

"These molecules are attractive because researchers have always wondered if pain could be targeted by a single drug—a magic bullet," he said. "It’s not likely at the level of the neurotransmitter, because different fibers use different transmitters. It’s unlikely a single transmitter blocker could work. But a drug blocking a certain population of pain fibers might be useful."

Basbaum has turned to an animal model—knockout mice lacking certain genes in this case—to find out. Several molecules, such as the signaling molecule protein kinase C (PKC), have been implicated in turning up the volume of a neurochemical signal in an injury downstream in the biochemical pain pathway in the spinal cord. Basbaum and his colleagues studied mice lacking PKC and found that the animals reacted normally to acute pain, but failed to develop neuropathic pain with sciatic nerve injury.

The University of Minnesota’s Mantyh and his co-workers have created an animal model of cancer pain. Reporting Dec. 15 in the Journal of Neuroscience, they described "a neurochemical signature in cancer pain entirely different than what we see with inflammatory and neuropathic pain."

"We looked at the genetic profile in areas of the brain and saw the protein profile is different in the cancer neuropathology," Mantyh said. "The cancer profile suggested that it was different from the inflammatory and neuropathic—different genes and proteins are turned on."

The next step would be to then target drugs at the particular cellular receptors and proteins involved in cancer pain, Mantyh explained.

Basic science is slowly turning up new drugs against pain. In the April issue of the Journal of Clinical Oncology, for example, UCSF researchers reported that prostate cancer patients in severe pain because of metastases to the bone may be able to reduce their need for morphine-based painkillers with a new anti-cancer drug called suramin. And Mantyh and his colleagues showed in the May issue of Nature Medicine that a drug, osteoprotegerin, slowed cell disruption in bone cancer, lessening pain.



             
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