*This page was produced as part of an undergraduate course at Davidson College.*
The Gene for Pain Tolerance
The Buzz-
Articles in the popular press started to emerge with the release of Dr. Jon-Kar Zubieta's (et al.) "COMT val158met Genotype Affects u-Opioid Neurotransmitter Responses to a Pain Stressor" in February of 2003. A complex name like that basically boils down to the fact that Zubieta's team had isolated and correlated the effects of a very common polymorphism in the COMT gene with response to pain. Simplified even further, this means that they have found a gene and a variation that could be responsible for differences in peoples responses to pain. The popular press deemed it the pain tolerance gene with articles toting headlines such as "Wimpy or stoic? Gene helps determine how much you hurt (Associated Press, 2003)" Research on the gene at this point is only in its preliminary stages and very little is known but thus far they have no evidence to suggest they are completely off the mark with their conclusion.
COMT?-
Yes, COMT or catechol-O-methyltransferase is a gene that controls the catechol-O-methyltransferase enzyme in its functioning. The sequence of the COMT gene can be viewed here at its locus as shown on NCBI, at this link. This enzyme is used to metabolize catecholamines, which are heavily linked to dopaminergic and adrenergic/noradrenergic neurotransmission, or endorphins (Zubieta et al., 2003). COMT functions by metabolizing dopamine and freeing receptors in the brain for the binding of endorphins to the u-opioid receptors, which lead to pain relief. The more potent the COMT enzyme that is functioning in the body the more dopamine that gets metabolized and more endorphins are allowed to bind.
Figure 1- A chime structure of COMT obtained from the Protein Data Bank, or PDB
What's this about a Polymorphism?- The polymorphism that is being investigated is one in the COMT gene referred to as val158met. The substitution for valine by methionine at codon 158 is a very common genetic occurence and "is associated with a difference in thermostability leading to a three-to fourfold reduction in the activity of the COMT enzyme. (Zubieta et al., 2003)" Three different results can come of this capacity for polymorphism with one allele being inherited from each parent. Codominance is observed in these alleles in their different occurences, those occurences being: val/val, met/met, or val/met. The Scientific Paper- The paper by Zubieta et al. attempted to explore the behavior of the brain and of the activity of the COMT enzyme as they differed among individuals with these different types of polymorphisms. 18 individuals of approximately 29 years of age were selected on the basis of gender and scan order and they found that they had selected 11 heterozygotes, 4 met homozygotes, and 3 val homozygotes. The individuals were subjected to positron emission tomography (PET) with the aid of [11C] carfentanil, a u-opioid receptor-selective radioactive marker. The receptor binding levels of the u-opioid receptors were tested in vivo during a sustained painful stimulus that was induced by the infusion of saline solution into the jaw muscles of the patients, causing a kind of TMJ. It was also tested during a sustained non-painful infusion of isotonic saline. Pain surveys, patient indications as to their level of pain, and other statistical tests were also administered to gauge their response. Below is an example of the sort of figure and testing that they used in the study to form the base of their reasoning... Figure 2- PET Scan: The highlighted areas show areas in which there was less u-opioid system activation in met/met individuals as compared to heterozygotes. The above image indicates that there was less u-opioid system activation in met/met individuals as compared to the heterozygote, indicating that less endorphins were at work than in an individual with the met/val genotype. Figure 3- PET Scan: The highlighted areas show ares in which there was more u-opioid system activation in val/val individuals as compared to heterozygotes. The above image indicates that there was more u-opioid system activation in val/val individuals as compared to the heterozygote, indicating that more endorphins were at work than in an individual with the met/val genotype.*Image permission pending from the authors of the scientific paper* I am making the summary of these results extremely general due to my unfamiliarity with biopsychology and due to the sheer complexity of the paper but what was observed was that individuals with the met/met genotype experienced more pain biologically and psychologically than individuals of the val/val genotype. Individuals who were heterozygotes experienced intermediate levels of pain somewhere between the two genotypes. Why did this occur? Less u-opioid system activation means that there were less endorphins present to numb the pain of the saline solution. More u-opioid system activation, on the other hand, means that there were more endorphins present to numb the pain of the saline solution. Why is this occuring? It is occuring because of the activity of the COMT enzyme, as stated before. They are not entirely sure of the mechanism but there is something about the COMT enzyme in val/val patients that makes it easier for it to metabolize dopamine and thus free up more space for endorphins to bind whereas the met/met patients were producing a form of the COMT enzyme that apparently was not metabolizing dopamine as well. The Popular Press - The popular press article discusses the aforementioned experiment while also alluding to the practical applications of these results. They even go as far as beginning to deem people "wimpy" or "stoic" based on their genotype as far as pain tolerance goes. Those that were val homozygotes were deemed stoic. While they were correct about what these tests indicated, they were not completely accurate in stating exactly what the tests were showing. They state that "Painkilling endorphins were much more active in these peoples brains (the stoics)." While this is true, this is something that has to be inferred from the test results as the PET scans do not show endorphin activity but merely activation of receptors. In addition, the article tends to jump to the conclusion that they have found for sure the gene for pain tolerance. While they have a strong suspicion that this is the gene, they are uncertain. The COMT gene is responsible for many different things in the body, even being linked to forms of schizophrenia. There are many other genes at work in the body that regulate this sort of thing and Zubieta himself cautions in the article that "Pain response clearly depends on more than a single gene. (Associated Press (CNN), 2003)" Zubieta also admits that he discovered in another study that women "tolerate pain better during the time of the menstrual cycle when estrogen levels are highest (Associated Press (CNN), 2003)." Thus, no one is really certain of the volume of different genes that contribute to pain response but they do believe that they have found a major contributor. The article also contained a few interesting tidbits of information that the scientific paper did not elaborate on such as Zubieta's estimate that "A quarter of the U.S. population carries the 'stoic' gene variation while another quarter has the gene variant that makes them super-sensitive to pain (Associated Press (CNN), 2003)." The article in and of itself was a good one as it did not make many huge leaps and it did an excellent job of simplifying an extremely difficult paper for public review. If you wish to view this article you may at this link. Conclusion- Though there are significant differences in what the popular press and scientific paper itself say, they seem to work together in this instance. The popular press attempts to be sensational but at the same time attempts to stay accurate, which is not always the case in the news. It is truly a beautiful thing when the media and science cooperate with accurate information, not only does it educate the public but it can also provide those attempting to understand the scientific venture in question with a more common viewpoint on which to build a foundation. Though one must keep in mind that this is all that it is, a foundation, the subject of genomics reaches taller than many could ever imagine. References- 1) Online Mendelian Inheritance in Man, OMIM (TM). Johns Hopkins University, Baltimore, MD. 116790: { 116790}: { 9/6/2003 . 2) "Wimpy or stoic? Gene helps determine how much you hurt." AP CNN 2/20/2003 3) Zubieta, Jon-Kar et al.: COMT val158met Genotype Affects u-Opioid Neurotransmitter Responses to a Pain Stressor. Science. Feb, 2003; 299(5610): 1240 4) Zubieta, Jon-Kar et al.: Regional Mu Opioid Receptor Regulation of Sensory and Affective Dimensions of Pain. Science. Aug, 2002; 293(5528): 311 Return to my Genomics Homepage by clicking here.Return to the Davidson Biology Homepage by clicking here. Return to Dr. Campbell's Homepage by clicking here.
What's this about a Polymorphism?-
The polymorphism that is being investigated is one in the COMT gene referred to as val158met. The substitution for valine by methionine at codon 158 is a very common genetic occurence and "is associated with a difference in thermostability leading to a three-to fourfold reduction in the activity of the COMT enzyme. (Zubieta et al., 2003)" Three different results can come of this capacity for polymorphism with one allele being inherited from each parent. Codominance is observed in these alleles in their different occurences, those occurences being: val/val, met/met, or val/met.
The Scientific Paper-
The paper by Zubieta et al. attempted to explore the behavior of the brain and of the activity of the COMT enzyme as they differed among individuals with these different types of polymorphisms. 18 individuals of approximately 29 years of age were selected on the basis of gender and scan order and they found that they had selected 11 heterozygotes, 4 met homozygotes, and 3 val homozygotes. The individuals were subjected to positron emission tomography (PET) with the aid of [11C] carfentanil, a u-opioid receptor-selective radioactive marker. The receptor binding levels of the u-opioid receptors were tested in vivo during a sustained painful stimulus that was induced by the infusion of saline solution into the jaw muscles of the patients, causing a kind of TMJ. It was also tested during a sustained non-painful infusion of isotonic saline. Pain surveys, patient indications as to their level of pain, and other statistical tests were also administered to gauge their response. Below is an example of the sort of figure and testing that they used in the study to form the base of their reasoning...
Figure 2- PET Scan: The highlighted areas show areas in which there was less u-opioid system activation in met/met individuals as compared to heterozygotes.
The above image indicates that there was less u-opioid system activation in met/met individuals as compared to the heterozygote, indicating that less endorphins were at work than in an individual with the met/val genotype.
Figure 3- PET Scan: The highlighted areas show ares in which there was more u-opioid system activation in val/val individuals as compared to heterozygotes.
The above image indicates that there was more u-opioid system activation in val/val individuals as compared to the heterozygote, indicating that more endorphins were at work than in an individual with the met/val genotype.
*Image permission pending from the authors of the scientific paper*
I am making the summary of these results extremely general due to my unfamiliarity with biopsychology and due to the sheer complexity of the paper but what was observed was that individuals with the met/met genotype experienced more pain biologically and psychologically than individuals of the val/val genotype. Individuals who were heterozygotes experienced intermediate levels of pain somewhere between the two genotypes. Why did this occur? Less u-opioid system activation means that there were less endorphins present to numb the pain of the saline solution. More u-opioid system activation, on the other hand, means that there were more endorphins present to numb the pain of the saline solution. Why is this occuring? It is occuring because of the activity of the COMT enzyme, as stated before. They are not entirely sure of the mechanism but there is something about the COMT enzyme in val/val patients that makes it easier for it to metabolize dopamine and thus free up more space for endorphins to bind whereas the met/met patients were producing a form of the COMT enzyme that apparently was not metabolizing dopamine as well.
The Popular Press -
The popular press article discusses the aforementioned experiment while also alluding to the practical applications of these results. They even go as far as beginning to deem people "wimpy" or "stoic" based on their genotype as far as pain tolerance goes. Those that were val homozygotes were deemed stoic. While they were correct about what these tests indicated, they were not completely accurate in stating exactly what the tests were showing. They state that "Painkilling endorphins were much more active in these peoples brains (the stoics)." While this is true, this is something that has to be inferred from the test results as the PET scans do not show endorphin activity but merely activation of receptors. In addition, the article tends to jump to the conclusion that they have found for sure the gene for pain tolerance. While they have a strong suspicion that this is the gene, they are uncertain. The COMT gene is responsible for many different things in the body, even being linked to forms of schizophrenia. There are many other genes at work in the body that regulate this sort of thing and Zubieta himself cautions in the article that "Pain response clearly depends on more than a single gene. (Associated Press (CNN), 2003)" Zubieta also admits that he discovered in another study that women "tolerate pain better during the time of the menstrual cycle when estrogen levels are highest (Associated Press (CNN), 2003)." Thus, no one is really certain of the volume of different genes that contribute to pain response but they do believe that they have found a major contributor. The article also contained a few interesting tidbits of information that the scientific paper did not elaborate on such as Zubieta's estimate that "A quarter of the U.S. population carries the 'stoic' gene variation while another quarter has the gene variant that makes them super-sensitive to pain (Associated Press (CNN), 2003)." The article in and of itself was a good one as it did not make many huge leaps and it did an excellent job of simplifying an extremely difficult paper for public review.
If you wish to view this article you may at this link.
Conclusion-
Though there are significant differences in what the popular press and scientific paper itself say, they seem to work together in this instance. The popular press attempts to be sensational but at the same time attempts to stay accurate, which is not always the case in the news. It is truly a beautiful thing when the media and science cooperate with accurate information, not only does it educate the public but it can also provide those attempting to understand the scientific venture in question with a more common viewpoint on which to build a foundation. Though one must keep in mind that this is all that it is, a foundation, the subject of genomics reaches taller than many could ever imagine.
References-
1) Online Mendelian Inheritance in Man, OMIM (TM). Johns Hopkins University, Baltimore, MD. 116790: { 116790}: { 9/6/2003 .
2) "Wimpy or stoic? Gene helps determine how much you hurt." AP CNN 2/20/2003
3) Zubieta, Jon-Kar et al.: COMT val158met Genotype Affects u-Opioid Neurotransmitter Responses to a Pain Stressor. Science. Feb, 2003; 299(5610): 1240
4) Zubieta, Jon-Kar et al.: Regional Mu Opioid Receptor Regulation of Sensory and Affective Dimensions of Pain. Science. Aug, 2002; 293(5528): 311
Return to my Genomics Homepage by clicking here.
Return to the Davidson Biology Homepage by clicking here.
Return to Dr. Campbell's Homepage by clicking here.