The Genetics Of Pain And Analgesia: From Molecules To Mice

• A relationship exists between initial sensitivity to pain and subsequent response to different drugs. Mice more sensitive to pain will be less responsive to analgesics, such as morphine, and vice versa. "They're either doubly lucky, or doubly unlucky," Mogil said.
• Involved genes are different in males and females. Sex differences have been known about but considered only in quantitative ways. "In addition to these apparent differences in magnitude, there appears to be fundamental neurochemical and genetic differences," he said. "Both feel pain, but they are responding differently, by activating different circuitry in the brain."Researchers and therapists recognize that variability plays a major role in assessing and treating pain -- the latter of which has depended on derivatives of willow bark (anti-inflammatory drugs) and poppy juice (opiods). "Arthritic people try over-the-counter remedies. Some work, some don't," Mogil said. "This implies that there are responders and non-responders. Wouldn't it be great if we could figure out why?"

Mogil, a professor of psychology and neuroscience, studies the genetic variability of pain, using inbred mice and rats doing "tail-flick tests" in hot water, for example.

Mogil has found that 50 percent of animals tested both feel and respond to pain, while 50 percent don't feel it or better tolerate it. He has found huge differences between strains -- some barely tolerate it, and some seem not to mind at all. Part of the differences, he said, reflect such factors as experience, age, stress and diet; part are from genetic biological inputs such as sex, hormones and stress; and part reflect genotype (inherited genes)."Our technique tells us about where the pain gene is located, but it doesn't tell us what gene it is or exactly where it is located," Mogil said. "If the genome is the United States, I know that for a particular gene trait there is a gene living in Iowa that is responsible. But I don't know what city, what neighborhood or what house. We can do more focused searches. Mostly, we are consulting Iowa's phone book to see what genes already known to live in Iowa look interesting."

The big phone book -- the Mouse Genome Project (like the human effort, an attempt to sequence the entire genome of this species) -- may speed the search, he said. Based on research to date and on the promise of findings to come, Mogil said there are three implications for the understanding and treatment of pain.

• Because of the variability of response, scientists know that some people really do or really don't feel pain when confronted by the same stimulus. "It seems this knowledge should lead to a destigmatization toward people who are pain sensitive," he said. "There really are differences in our responses to pain."
• A pre-operation blood test may soon help to determine a person's genetic response to pain, allowing for the correct strategy for treating post-surgical pain.
• When the "volume knob of pain" is located, gene therapy could deliver a "better, more advantageous form of a gene" to an affected area to reduce or eliminate chronic pain.

Mogil in 1998 received the John C. Liebeskind Early Career Scholar Award from the American Pain Society and the Neal E. Miller New Investigator Award from the Academy of Behavioral Medicine Research. Reporting in the Journal of Neuroscience in October 1997, Mogil identified a chromosomal location linked to pain response specific to female mice.