The cellular processes that cause and transmit pain appear to be fundamentally different in males and females. If so, it is likely future painkillers, at least for certain types of pain, will be sex-specific.
Biology tends to be parsimonious, maintaining features as long as they work. This is a likely explanation for male nipples, for example – they may serve no useful purpose, but a common architecture for all humans is more efficient than to evolve unnecessary differences. Although there are differences in dosage requirement for certain painkillers, this has usually been attributed to sex hormones interfering with the drug's effectiveness, rather than more fundamental differences.
Or at least they were, until three years ago, when Canadian scientists revealed that cells known as microglia transmit pain in male mice, but not in females. Early evidence at the time suggested female mice were probably using T cells instead.
The discovery was so unexpected, and the reasons so mysterious, it naturally aroused plenty of suspicion and the need for independent verification, as well as confirmation the same is true for humans.
A paper in the Journal of Neuroscience extends the original findings by showing dopamine D5 receptors are important for the way male, but not female, mice process pain.
"For the same magnitude of pain in a male and a female, the mechanisms that drive pain seem to be remarkably separate," senior author Dr Ted Price of the University of Texas, Dallas, said in a statement. "We've made a cellular change that completely reverses the genesis of the chronic pain in only the male.”
D5 receptors are triggered by dopamine. When mice were genetically engineered not to have them, the males showed much weaker responses to pain stimulus than their wild-type brothers, but female mice reacted the same way whether engineered or not.
We can't ethically engineer people, but tests can be done on our tissues. If the results are repeated, Price said, “you could make a D5 antagonist drug to treat pain in men."
He added: "It leads me to believe that it's fairly likely we'll want to make male- and female-specific drugs for chronic pain."
D5s account for a small part of pain transmission even in males, so the principle of their difference (indicating others probably also exist) may be more important than blocking this particular channel. Price acknolwedged the discovery might never have been made without guidelines requiring testing on animals of both sexes.
The differences may apply to areas of biology other than pain, and Price thinks it may explain why many preclinical studies, often done only on male animals, fail to translate to something that works in clinical trials. It may also explain why chronic pain is more common in women than men.