RELIEF IN SIGHT: RESEARCHERS LOCATE GENE MUTATIONS RESPONSIBLE FOR CHRONIC PAIN
ATLANTA, October 15, 2006 - Molecule by molecule, neuroscientists are identifying the biological underpinnings and molecular origins of chronic pain. These include advances in understanding crucial genes, electrical currents, nerve fibers, and receptors for energy sources in nerve cells.
This new knowledge eventually could lead to better treatment for the 50 million Americans who suffer from several chronic pain syndromes. For these people, pain lasts for months or years, can evade moderation by traditional therapies, and often worsens as time progresses.
"With no knowledge of the exact underpinnings, there is, as yet, no cure for neuropathic pain," notes Stephen Waxman, MD, PhD, at Yale University School of Medicine. Waxman focuses on erythromelalgia, which causes severe pain in the feet and hands. "This particular painful neuropathy can be so debilitating that some individuals seek to end their lives out of sheer desperation," he says.
Because it is inherited, the erythromelalgia is genetically based. By analyzing DNA samples from patients with the syndrome, Waxman and his research team pinpointed the precise location of mutations in the gene, labeled Nav1.7, that is responsible for erythromelalgia.
The mutated Nav1.7 gene distorts the tiny, gated pores, also called channels, through which sodium molecules enter the brain cells, or neurons. Passage of sodium ions through these channels generates electrical nerve impulses-including those that produce normal painful sensations as well as the abnormal pain of erythromelalgia.
In the laboratory, Waxman's team measured the electrical currents produced by the mutant Nav1.7 sodium channels and discovered that the pain signaling neurons containing the Nav1.7 mutation turned on more easily and fired nerve impulses at higher than normal rates.
"In other words, mutations in Nav1.7 channels lowered the threshold for activation, causing neurons to become hyperexcitable, and produce rapid bursts of nerve impulses in response to normally non-painful stimuli," explains Waxman.
"The brain, in turn, interprets such nerve impulses as signaling a painful stimulus," he adds.
A major culprit in chronic neuropathic pain is the abnormal functioning of the so-called pacemaker ion channel in neurons, says Sandra Chaplan, MD, of Johnson & Johnson Pharmaceutical R&D in San Diego. Pacemaker ion channels -- like the heart's pacemaker node that is responsible for the regular heartbeat -- can generate continuous electrical impulses, or action potentials. But in the sensory nerves, they normally don't. "Unlike their function in the heart, pacemaker ion channels in neurons do not lead to continuous nerve firing in sensory nerves except when they are injured," explains Chaplan.
"Our research has shown that injury causes an increase in pacemaker currents that appears to play a critical role in the constant electrical activity of damaged sensory nerves," she adds. Neuropathic pain symptoms vanished in animal models of nerve injury when they were treated with experimental drugs designed to slow or stop the pacemaker currents, raising the possibility that such an approach may be applicable to humans.
New findings from Anne Louise Oaklander, MD, PhD, of Harvard Medical School, focuses on complex regional pain syndrome (CRPS), which is characterized by long-lasting pain and a dysfunction of small blood vessels that can cause the painful arm or leg to swell, blister, or change temperature or color.
"CRPS can be triggered by major injuries such as a broken bone or by seemingly minor injuries such as an ankle sprain," Oaklander says. "The hallmark of CRPS is pain severity out of proportion to tissue damage, a discrepancy that causes many people -- including physicians -- to wonder if patients have a psychological disorder or are just malingering."
Her research, along with studies from two other laboratories, recently showed that CRPS is one of the neuropathies, and suggests that CRPS results from persistent damage to small-fiber nerve endings in the patient's body.
"The job of these small fibers is to transmit pain messages and to open and close the blood vessels that influence skin color and temperature," she says. Because of small fibers' function in the body and previous studies linking small-fiber dysfunction or loss to shingles, diabetes and most other neurological pain disorders, Oaklander had suspected that small fibers might be damaged in CRPS.
Analysis of skin samples showed that they were. Oaklander and her research team at Massachusetts General Hospital counted the nerve endings in skin biopsies from people with CRPS as well as individuals without CRPS but who had similar symptoms as a result of severe arthritis. Samples were taken for non-painful as well as painful areas.
In CRPS patients, the skin from the painful areas had 25 to 30 percent fewer nerve endings than did biopsies from the individuals' non-painful skin areas.
"Sensory testing suggested that the nerve losses were associated with such abnormalities as perceiving a light touch to be painful," she says. "No nerve-ending loss was found in the arthritis sufferers, suggesting that chronic limb pain, swelling, or disuse alone are not enough to cause the nerve loss seen in the CRPS patients."
Recent studies by Michael Jarvis, PhD, of Abbott Laboratories in Illinois, indicate that that adenosine triphosphate (ATP), already known to be the energy source for all living cells, also acts on two groups of newly discovered receptors on cells to communicate important nerve signals, including the sensation of pain.
The cell receptors that specifically bind ATP are labeled P2X, calcium permeable channel proteins, and P2Y, receptor-messenger signaling proteins. Acute pain occurs when ATP binds with and activates the P2X3 receptors. Jarvis has found that activation mediates the painful effects of ongoing inflammation when P2X3 was either blocked or deleted in rodent models.
Also, when Jarvis administered A-317491, a potent and highly selective P2X3 blocker, to the lab animals, ATP's acute painful effects were blocked, and the painful effects of acute and persistent peripheral inflammation were reduced.
"This novel compound also reduces pain associated with permanent nerve injury indicating that activation of P2X3 receptors may also play a role in chronic nerve-injury pain states like diabetic neuropathic pain," says Jarvis.
"While these data indicate that activation of P2X3 receptors contribute to the sensation of pain, this receptor is not the only mechanism by which ATP may modulate pain signaling in the central nervous system," he adds.
Activation of some P2Y receptors can prime other pain modulating mechanisms, such as the TRPV1 receptor, a cell surface protein that is sensitive to the active ingredient in hot chilies, and thereby enhance pain sensitivity, Jarvis says, opening the possibility of more effective treatments.
Other studies in pain look at another member of the ATP receptor family, P2X4 receptors, which proliferate following nerve injury. Activation of P2X4 receptors leads to the release of brain-derived neurotrophic factor (BDNF) from microglia, support cells in the central nervous system, which ultimately results in disinhibition, and, in some cases, net excitation, of these neurons.
Normal inhibitory mechanisms in the body's pain processing network can be suppressed, says Michael Salter, MD, PhD, of the Hospital for Sick Children in Toronto. "The loss of inhibition is in the spinal cord, not the brain," he says.
When the inhibitory mechanisms are blocked, "excessive amplification occurs in the pain processing network," says Salter. "The amplification is akin to excessively turning up the volume of your stereo." This greater understanding could lead to a more targeted treatment for chronic pain.