Among all the pesky, pitiless four-letter words in the English language the most common and least scrutable is P-A-I-N. So it's glad tidings when a new gene, and the protein it encodes, surface to explicate nociception - the brain's sensation of perceiving "ouch" and "agony" - acute and chronic pain.

A paper in today's Science, dated Feb. 21, 2003, bears the revelatory title: "COMT Val(158) Met genotype affects m-opioid neurotransmitter responses to a pain stressor." Its first author is neuroscientist and clinical psychiatrist/radiologist Jon-Kar Zubieta, at the University of Michigan's Mental Health Research Institute.

"This particular paper deals with the very common genetic polymorphisms," Zubieta told BioWorld Today. "They are what we call the single nucleotide polymorphism, or SNP. By changing just one amino acid, methione substitutes valine in the gene that codes for an enzyme, catechol-ortho-methyl transferase - COMT for short.

"Our basic finding in this Science report," Zubieta continued, "is that all individuals have this enzyme to metabolize neurotransmitters in the brain. And depending on how many of each form of the COMT allele you inherit, you will have different mechanisms. For example, if you have one allele coming from your mother and one from your father, and both of them are the met-met [methionine/methionine] form of the enzyme, that will confer the lowest activity to metabolize the so-called catecholamines. If you have one of each [methionine/valine], you have intermediate activity, and the val-val form gives you the most active.

"Depending on the activity of this enzyme - which one of the genes you have, whether met/met, val/val or met/val - your activity to activate this pain and stress suppression system is in the brain's opiate system. That's the difference. The met/met people have the lowest capacity to activate the endogenous opiates.

"This is one of the very few research papers that really correlates genes to neurochemistry changes in humans," Zubieta went on, "which we measure directly with PET [positron emission tomography] the actual chemicals being released, and how the so-called phenotype is expressed in a particular individual. We take it all the way from gene to molecular neurobiology to behavior. So it's unique in that sense."

Pain-Braving Heroes Can't Fool System

"This speaks to individual differences," Zubieta observed, "in how people are able to suppress or react to pain and by extension to other stressors. Some people may be more vulnerable to deal with pain than others, or may be more vulnerable to developing mood symptoms or anxiety symptoms when they are subjected to stress. And it speaks to those factors, and how they impact on the later development of illnesses, pain conditions or depression, which is frequent in chronic pain. That's where I think this work is leading to."

This work recruited 29 human volunteers, 15 men and 14 women, aged 20 to 30. Some were students, all of them answered advertisements; all were highly educated. The women were PET-scanned during the phase of their menstrual cycle when their estrogen levels were lowest. Zubieta and his team had previously shown that the hormone affects the mu-opioid response.

"The mu-opioid receptor mediates the action of endorphins and enkephalins in the brain," Zubieta recounted. "Three receptors mediate the actions of the endogenous opioids. They are delta, kappa and mu. The mu is very important for pain, and for stress responses - anxiety and depression. Some of these pathways have been associated with the effects of drugs of abuse - alcohol and cocaine for example. And drugs of abuse are known to interact with stress, so we are working in that direction as well.

"Dopamine is one of the neurotransmitters that has been involved in rewards, and the effects of cocaine," Zubieta noted. "But dopamine also has a much broader effect in mediating salients - rewarding and nonrewarding such as pain.

"We used a model of temperomandibular pain, whereby we infused small amounts - about 1.5 milliliters of 5 percent hypertonic saline solution - into the jaw muscle, using a very thin needle, and it hurt. We maintained the painful infusion for over 20 minutes. Then we asked the participants to rate the intensity of the pain. The infusion is calibrated to induce a pain that rates about 40. But each person is different. So every 15 seconds we weighed the pain, by an electronic scale, and that rating then went into the computer, which keeps the infusion in solution just enough so the pain is constant throughout the experiment. It's very difficult to fool this system, because we can tell how much pain is going in, and how much rating people are giving. That's where we look at the opiate system as well when we analyze the PET readout.

"The results showed that the differences in volunteers' pain sensitivity paralleled the COMT activity of their genotypes," Zubieta reported. "The study showed that people with two copies of the met' form of the COMT gene had a much more pronounced response to pain than those who carried two copies of the val' gene form. And those with one copy of each variant had a pain tolerance somewhere between the responses of the other two contingents. So it's very difficult to fool the system. You could do it in theory but it would hurt you a lot. So if you said with bravado, I'm not feeling anything,' and rate the pain low, the infusion rate will rise higher. As soon as you stop the infusion, the pain goes away in seconds."

Scoping Female Gender's Pain Sensitivity

"Chronic pain conditions are very poorly understood," Zubieta pointed out. "Some are more frequent in women than in men. Some conditions like temperomandibular pain, or fibromyalgia, are much more frequent in women. No one understands why. In our ongoing research, we are now continuing to study women mostly, trying to understand the interactions between genetics and hormones, for example.

"That's one issue we're pursuing. Another is how medications, analgesics, can affect the systems. The main thing the brain will tell us about treatment targets is going to be looking at the chemistry. Using MRI and PET," he concluded, "we'll be able to pinpoint them."