You may soon be able to get painkillers that take into account your age, sex and pain threshold, and compensate for any side effects or possible predisposition to addiction.
Painkillers Designed Especially for You?
Scientists Examine the Genetic Basis of Pain to Help Patients More Effectively
By ANDREW CHANG
May 11, 2005 -- As part of his research, Dr. Jeff Mogil scoops up lab mice, one at a time, into specially designed cardboard and cloth pockets and holds each of them over a vat of hot water.
The mice don't seem to have a problem getting in the pockets, Mogil said. "It's dark and smelly in there."
But the pockets aren't quite big enough to hold the entire mouse. The tail hangs outside — allowing Mogil to dip the tail into the 120-degree Fahrenheit water. Then he measures how long it takes for the mouse to flick its tail out.
Each mouse takes a different amount of time to react. And Mogil, a professor of pain studies at McGill University in Montreal, is trying to find out why.
Scientists have long recognized that all living things, from lab mice to human beings, have a range of pain sensitivity, and they're starting to discover the genetic basis of these differences. Doctors are on the cusp of a revolution in pain relief, they say.
Today, patients undergoing surgery get painkillers in a standard dosage mainly determined by body weight. But "there may be a point in time when we may be able to tell which patient responds to which type of pain medicine," said Dr. Sunny Anand, director of the Pain Neurobiology Laboratory at Arkansas Children's Hospital in Little Rock.
A patient could get a regimen of painkillers that will take into account his or her age, sex and pain threshold, and compensate for any side effects or possible predisposition to addiction.
"I don't think it's science fiction," Anand said. "Within the next five years we will be there."
Brain and Sex Differences
There has already been some progress in understanding the genetic basis of pain. One of the primary areas of discovery has been the most fundamental: the difference between men and women.
Many scientists believe that male and female brains differ in architecture, and consequently, "some of the genetic differences that create sex brain differences may make pain vulnerability different," said Dr. Lonnie Zeltzer, director of the pediatric pain program at UCLA Mattel Children's Hospital.
For example, she says she found that mothers who are highly sensitive to pain tended to have daughters who are highly sensitive to pain, but the mother's level of sensitivity seemed to have no effect in sons. She said she also found that while pain tolerance generally increases with age, boys' pain tolerance rises in late puberty while girls' pain tolerance drops.
Different areas of men's and women's brains light up during "arousal" events, she said. Using an earthquake as an example, she said women tend to remember more of the details, such as what day it was or what somebody was wearing, whereas men would remember more of the overall event.
Zeltzer said such disparities might be due to hormones such as testosterone. But the results of a seven-year study involving eight laboratories released earlier this year suggest another genetic basis for these differences — not only between sexes but individuals.
A Key in COMT?
Dr. William Maixner, one of the scientists involved in the study, said they found that individuals who had a variation in a gene responsible for creating an enzyme called COMT were likely to be more sensitive to pain.
COMT breaks down the stress hormone ephinephrine, and if the gene doesn't produce enough COMT, ephinephrine continues to circulate throughout the body. When that happens, the body is more sensitive and more likely to develop chronic pain.
Maixner, director of the Neurosensory Disorders Unit at the University of North Carolina at Chapel Hill's School of Dentistry, said women in general have lower levels of COMT because the enzyme is regulated by estrogen.
The study also suggested the genetic variation that produced less COMT could be one of the causes of chronic pain.
The More Sensitive Sex
The COMT discovery echoes the general notion that women are more sensitive in general — not only to pain, but other sensations.
Men have "morphine-like proteins that deal with this flight-or-fight response that makes them more pain-tolerant," Maixner said. "Women don't have the same capacity to engage this system." Their bodies produce a different type of protein to deal with pain, he said
Different areas of men's and women's brains light up during "arousal" events, she said. Using an earthquake as an example, she said women tend to remember more of the details, such as what day it was or what somebody was wearing, whereas men would remember more of the overall event.
Zeltzer said such disparities might be due to hormones such as testosterone. But the results of a seven-year study involving eight laboratories released earlier this year suggest another genetic basis for these differences — not only between sexes but individuals.
A Key in COMT?
Dr. William Maixner, one of the scientists involved in the study, said they found that individuals who had a variation in a gene responsible for creating an enzyme called COMT were likely to be more sensitive to pain.
COMT breaks down the stress hormone ephinephrine, and if the gene doesn't produce enough COMT, ephinephrine continues to circulate throughout the body. When that happens, the body is more sensitive and more likely to develop chronic pain.
Maixner, director of the Neurosensory Disorders Unit at the University of North Carolina at Chapel Hill's School of Dentistry, said women in general have lower levels of COMT because the enzyme is regulated by estrogen.
The study also suggested the genetic variation that produced less COMT could be one of the causes of chronic pain.
The More Sensitive Sex
The COMT discovery echoes the general notion that women are more sensitive in general — not only to pain, but other sensations.
Men have "morphine-like proteins that deal with this flight-or-fight response that makes them more pain-tolerant," Maixner said. "Women don't have the same capacity to engage this system." Their bodies produce a different type of protein to deal with pain, he said
"If you give [opioid-based painkillers like] morphine or Dilotid in fact you have to give more to women than men because they have a lower density of opioid receptors," said Zeltzer. "Women tend to require more than men to achieve the same type of relief."
Other Genetic Differences
This sort of genetic predisposition isn't limited to gender though. Scientists have long known that people with fair skin and red hair are generally more sensitive to pain and also more resistant to opioid-based painkillers.
In the early 1980s, scientists discovered as many as 10 percent of Caucasians have a variation in a gene that makes them unable to make the enzyme that would allow them to metabolize codeine, another painkiller.
"Giving them codeine is useless, maybe worse than that because they might get side effects," Mogil said.
And Anand says there is some recognition that genetics can also determine the effectiveness of certain types of antidepressants called SSRIs.
Nature and Nurture
But genetics is far from the only thing to determine a person's susceptibility to pain.
In his tests, Mogil says even more important than genetics in determining how long the mouse would leave its tail in the 120-degree water was the experimenter — although he doesn't know why.
"When I do the testing, the latencies are short," he said. "When my grad students do it, they're longer."
The order of testing also matters, he said. The first mouse out of a cage of four takes longer to remove its tail than the fourth. He thinks there is some sort of communication that takes place.
Zeltzer, who studies pain in children, said pain vulnerability is a complex interaction between genes and environment. "It's very much an interplay of nature and nurture," she said.
But for all doctors, this research is a sign that the old prescriptions may soon become obsolete. It's getting to the point where they won't be able to say "just take two and call me in the morning" anymore.
据ABC新闻网5月11日消息，加拿大蒙特利尔麦吉尔大学的Jeff Mogil博士利用老鼠研究生物体疼痛产生的机理，并有望借此制造出适合不同病人的止疼药。实验中Mogil博士把不同老鼠分别装在一个袖珍口袋里，并把它们放在一大桶热水上，老鼠的尾巴露在外面。
Mogil说，袖珍袋子不透光，只能容纳一只老鼠的身体部位。把老鼠的尾巴放入华氏120度的水中，然后测量出老鼠经过多长时间才会把尾巴从热水中抽出来。
每只老鼠的反应时间都相同。Mogil博士通过此试验研究生物体产生疼痛的机理。
科学家很早就知道世界生物，从老鼠到人都有不同的疼痛敏感范围。现在科学家们试图找到产生这种现象的生物体基因差异。如果该研究有所突破，医生对止疼药的使用将更有效。
目前，全世界的病人进行手术之前都会根据自身的重量来决定接受多大剂量的止疼药物。美国阿肯色州儿童医院疼痛神经生物学负责人Sunny Anand博士说：“医生很难辨别到底哪些止疼药适用于特定的患者。”
医生可以根据止疼药的副作用、患者的年龄、性别、及其疼痛感来决定给患者服用多大剂量的止疼药。
Anand表示，他认为五年之内医生就可以根据病人的基因决定最佳的服用剂量。
大脑与性别差异
先前科学家已经对人类疼痛敏感度的差异有了一定的认识。最明显的一条就是科学家发现男性与女性对止疼药的敏感度不同。许多科学家相信产生此现象的主要原因是，男性与女性的基因差异导致大脑结构出现轻微区别，从而产生以上现象。
如果母亲对止痛药十分敏感，那么她所生的女儿也很可能对止疼药敏感，但是她生的儿子却不一定会。人类通常随着年龄的增长而对止疼药的敏感度降低，女性尤其如此，但男性随着身体成熟反而会出现对疼痛更为敏感的反弹现象。
这些现象可能是因为男性和女性的大脑接受外界刺激的区域不同。比如说女性通常会记得事情的细节，像事情发生的时间；人物的穿着等，但是男性一般会记得整个事情的经过。
荷尔蒙也有可能产生这种效果，比如睾丸激素。但是科学家发现即使是同性的个体之间也存在很大差异。
北卡罗莱纳州立大学神经感觉混乱研究负责人WilliamMaixner博士也参与了该研究。他说：“人体基因中有一部分负责产生一种叫做COMT的酶，如果某人这部分基因与常人不同，他就很可能对疼痛更为敏感。
COMT主要负责破坏产生疼痛感的荷尔蒙，如果生物体没有产生足够的COMT，这种荷尔蒙就会在身体里循环，不断使生物体产生疼痛感，患者由此就更容易产生疼痛感。
Maixner说道，女性体内COMT含量普遍比男性少，因为她们体内的雌激素抑制了这种酶的产生。
通过对COMT的研究科学家极有可能发现人类患慢性疼痛症的原因。
科学家对COMT的研究反驳了人们通常认为女性对疼痛更为敏感这一观念。
男性体内含有一种类似于吗啡的蛋白质，这种蛋白质可以帮助男性忍受更大的疼痛。女性则没有此类蛋白质。
产生这种现象的原因可能是母亲必须更好的保护她们的孩子，她们必须对疼痛更为敏感。
这些发现对外科医生十分有用。男性体内不仅能产生出类似于吗啡的蛋白质，他们对于此类蛋白质的敏感程度也比女性强。举例来说，如果医生需要向患者体内注射此类蛋白质，女性需要的剂量就比男性大，因为女性对这种蛋白质不如男性敏感。
其它基因差异
患者对疼痛的敏感程度决不仅仅限于性别差异。科学家很早就发现，白皮肤红头发的人通常都对疼痛更为敏感，并且他们需要止疼药的剂量也更大。
早在八十年代，科学家就发现百分之十的白种人都缺少一种基因，这种基因主要产生一种让患者能够吸收止疼药可待因的酶。所以，给这些人注射可待因毫无用处，并且注射后还会出现副作用。科学家也发现遗传基因可以决定镇静剂SSRIs是否对患者起作用。
人类对于疼痛的敏感程度也不只是由基因单一决定。在Mogil的试验中，他发现对老鼠进行测试的人也会对试验结果产生影响。当他亲自做这个试验时，所记录的时间普遍偏短。但是当他的学生做这个试验时，老鼠反应的时间则普遍偏长。
取出老鼠的顺序也会对实验结果产生影响，第一只被试验的老鼠用去的时间通常比最后一只试验的老鼠用的长。
Zeltzer是一位主要研究儿童疼痛学的科学家，他说道疼痛是生物体自身基因和外界环境相互作用的结果。它与生物体的基因和生长过程都有很大关系。
对于医生来说，这项试验很可能是老式止疼药物被废除的信号。医生将不能简单地告诉病人：“服用两粒止痛药，明早来见我。”
