Chronic pain is considered an illness on its own, beyond the disease that causes it. Now specific genes have been identified that determine how much it hurts.
By JUDY SIEGEL-ITZKOVICHmarshall devor 248.88(photo credit: Judy Siegel)
Everyone knows what pain is - from giving birth, a stubbed toe, an infected tooth, a burn, surgery or a fall - and the physiological mechanism is well understood. But chronic pain, from which nearly 20 percent of the population suffer - migraines, rheumatic disease, cancer, neuropathy, "phantom limb" syndrome, spinal problems and others - is considered a fully fledged "illness" in addition to the pathologies that cause it.
Pain is one of the most persistent health problems faced by humanity. Although chronic pain itself is not life-threatening, it can lead to depression and suicide.
Unfortunately, the mechanism involved in chronic pain is still not completely understood and thus it's not preventible or curable, but neuroscientists like Hebrew University Prof. Marshal Devor continue to make progress in trying to find answers. He has come to one big conclusion - that specific genes determine why two patients with exactly the same stage of the same disease may experience different amounts of pain. This variability from one person to the next is a major puzzle.
Prof. Marshall Devor, 60, who was born in Toronto and studied at Princeton and MIT, came on aliya 30 years ago. Today he works in the department of cell and animal biology at HU's Institute of Life Sciences, and his lab has published extensively on pain, neurophysiology, neuroanatomy, genetics and animal behavior.
THE VARIABILITY in the sensation of acute pain, says Devor, is clear when a slap in the face that provokes sobs in one person is laughed off by another. Every individual has a different pain threshold, and variability in expression has also been attributed to cultural and psychosocial factors such as personality and upbringing. Women in one country may scream in delivery rooms while those in another are silent. In some countries, he notes, people "don't hesitate to express their pain, while in others, children are taught to be stoical. There are also big differences between men and women, girls and boys... Is it possible that the socialization of boys and girls actually alters the amount of pain experienced, and not just how pain is expressed?"
Devor stresses that pain cannot be shared. "Pain is inherently a private, first-person sensory and emotional experience. It is felt by the person; even using delicate instruments, a doctor cannot know exactly how intense is the suffering of a victim; he can only observe outward behavior and language." However, pain can be measured subjectively by sufferers on a scale of 0 to 10. Children can describe the amount of pain they feel using a graphic scale of faces. Animals can feel pain, says Devor, and can be judged by their reactions such as pulling a paw away.
Advances in non-invasive brain imaging such as functional magnetic resonance imaging (fMRI) or positron emission tomography (PET) may soon make it possible to know objectively whether someone is faking or exaggerating his pain; the amount of neural activity, he says, rises and falls in certain parts of the brain to reflect the amount of pain, but the amount of pain felt can be changed by hypnosis, pain-killing drugs and even anticipation. One can also observe signals indicating that a loved one of the person you are testing is in pain. "Just knowing that a loved one is suffering affects your own brain, and you can see such empathy in monkeys and even mice."
Pain, he adds, "is both friend and foe. Acute pain is for the most part a friend, as it warns of a problem; but if a part of torture, such pain is of course a foe." Chronic pain is a foe as well, and while it is defined as suffering that lasts at least six months, the average is at least four years.
Pain "resides at the interface of body and mind; only people who are conscious can feel pain." It has been defined by pain experts as "an unpleasant sensory and emotional experience associated with actual or potential tissues damage, or described in terms of such damage."
Neurons in the spine, explains Devor, have long axons. A stimulus generates electrical impulses, and the signal goes into various parts of the cerebral cortex and other brain regions called the pain matrix. The stimulus affects specific patches of brain cells. Scientists don't know how pain is experienced in the brain. It is initiated by physical stimuli translated into electrical signals, the neuroscientist continues, "but if you stimulate nerve fibers electrically along the path, a person will say he feels a sensation, not in the nerve but in his hand, for example. If a nerve is injured, or you have a viral infection or inflammation, the injury site becomes an abnormal source of electrical impulses. They run to the brain and are perceived there."
Phantom limb pain is very puzzling. If a hand or arm has been amputated or lost - as happened to Admiral Lord Nelson (who died in the 1805 Battle of Trafalgar) - one can still feel pain in the missing part. The brain sends signals down the spinal cord, causing the victim to feel pain without the signal reaching the limb.
ONE CAN also be seriously injured without feeling pain: Devor describes a drawing from the Battle of Handak, which involved a schism between Shi'ite and Sunni Muslims. The leg of a soldier in the battle was severed and he goes on to use his limb as a weapon, as he feels no pain. This phenomenon has also been documented in people who suffer severe injuries in road accidents. Animals too can suppress pain caused by sudden events. This is called stress-induced neuralgia.
One's expectations also affect pain perception. If one goes to a non-medical "healer" who waves his hands above your body or ties a red string around your wrist, or to a clergyman who gives you a blessing, these can relieve pain, Devor says. Faith and superstition can actually relieve pain. "The belief that a red string will relieve pain can actually relieve pain. It's called placebo analgesia, and it's real and sometimes powerful. It could even be as effective as an injection of morphine." This ability, he suggests, "was given to the brain to suppress pain in times of emergency. It is endogenous, designed to let the body fight and struggle, and lick the pains later. It is brain circuitry of relief."
An experiment was conducted to allow Christian subjects to meditate on either of two photos - an ordinary woman and the Virgin Mary. The images look similar, and the subjects were either devout Catholics or atheists. Both were then exposed to a heat stimulus. The image of Mary had no pain-relieving effect in the non-believer group, but it did relieve pain in the devout, recalls Devor.
He notes that for many years, pediatricians and parents were unaware that newborn infants felt pain because they thought their nervous systems were still undeveloped - or that they wouldn't remember it anyway. For that reason, when painful procedures were conducted, no analgesia was offered. But more recent studies have shown that newborns are indeed capable of feeling pain, and not giving anesthesia before a painful procedure is now considered a form of abuse.
"We don't know how much newborns remember pain or for how long, but an Israeli study showed that eight-year-old boys who have been circumcised cry much more than girls after they get childhood vaccinations."
IN ADDITION to socialization and other psychosocial and environmental factors, says Devor, differences in the wiring of our individual brains due to gene variations are responsible for how people respond to pain.
Rare familial diseases inherited by some people but not by others give good evidence of this, as have identical-twin studies. More recently, scientists have been identifying specific genes that make it more likely that one will suffer pain in response to injury or disease, says the neuroscientist.
New knowledge of how genes affect pain could not only lead to improved pain relief but also eliminate the stigma of being a "crybaby" in people who say their condition is more unbearable than that suffered by others with the same disease; the difference can be explained by their DNA.
Not all 25,000 genes in each cell affect pain sensation, he says. "For some genes, however, there are rare variants [mutations] or common variants [polymorphisms] that do affect the functioning of the proteins encoded... At present, we have no idea how many genes" affect pain response. Some pain genes may have no effect on pain at all except under unusual circumstances, Devor says, such as at high altidues or if your sister-in-law made you particularly exasperated. In this case, the genes' influence interacts with the environment. Certain pain relievers such as opiods, he concludes, relieve pain in one sex or another.
"The genetic revolution has only just started to affect the field of pain science and medicine. There is well-founded optimism abut the potential power of linkage analysis and association studies... The payoff in terms of new therapeutic options is likely to be not too far down the road. That is certainly good news for the one in five prople who suffer from chronic pain."
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