When it comes to pain, not everyone responds the same way. New findings are helping to unravel why this is the case. Researchers writing in the current issue of the journal Science report that variations in a single gene significantly affect the function of the brain's natural painkilling system, and may thus account for some of the observed variability in pain tolerance.

Natural pain moderation depends on the activation of a brain cell surface protein called the mu-opioid receptor. When we experience pleasure the brain is flooded with dopamine and the production of chemicals needed to activate the receptor drops off. Jon-Kar Zubieta of the University of Michigan and his colleagues studied the gene that controls the production of catechol-O-methyl transferase (COMT), an enzyme that patrols the brain's interstices, breaking down dopamine and clearing the way for painkilling chemicals to switch on the mu-opioid receptor.

There are two variations, or alleles, of the COMT gene, val and met, and the COMT enzyme they encode differs by one amino acidvaline or methionine, respectively. Everyone has two copies of the gene, one from each parent. Because valine COMT breaks down dopamine more effectively than its methionine counterpart does, Zubietas team surmised that individuals carrying two copies of the val allele would be best able to metabolize dopamine, thereby activating the brain's painkilling system most effectively.

To test that hypothesis, the researchers conducted brain scans on volunteers while injecting salt water into their jaw muscles, mimicking a painful condition known as temporomandibular joint disorder. As predicted, subjects possessing two copies of met were far less tolerant of the pain caused by the injections than those with two val alleles; those carrying one of each fell in the middle. Last week, at the annual meeting of the American Association for the Advancement of Science in Denver, Colo., Zubieta presented preliminary data suggesting that the painkilling system of women is further affected by monthly variations in estrogen. When estrogen levels are lower, he believes, the brain is less able to subdue pain. "All of this work is helping tell us how important individual differences are in the experience of pain and other significant stressors," Zubieta comments. "Our findings and those of other groups underlie the need to think about pain, particularly prolonged or sustained pain, as the result of complex interfaces between injury and our own capacity to regulate its severity and significance."