Sex equality means nothing when it comes to pain relief.
Morphine is not very potent in female rats, and a new study helps explain why. In their midbrains, females have fewer of the receptors that sense the feel-good drug, rendering morphine “remarkably ineffective,” according to a report published December 24 in the Journal of Neuroscience.
Opioid-based narcotics, such as morphine and codeine, are some of the most widely prescribed drugs for human pain management. The drugs are detected by proteins in the brain called opioid receptors, which bind to the drugs and trigger pain relief. But earlier studies in humans and rats have suggested that when it comes to pain-fighting medications, males and females are not created equal.
Female rats are known to require twice the amount of morphine as males to get comparable pain relief, says study author Anne Murphy of Georgia State University in Atlanta. But much of the research on pain relief has been conducted on male animals or in men. “What about females? No one’s bothered to ask these questions,” she says.
A part of the rat brain called the periaqueductal gray is important for pain relief. Earlier studies in male rats have shown that many opioid receptors are located in this particular midbrain region. Murphy has dubbed the region the “Mecca for morphine.”
Murphy’s team found that male rats have significantly more opioid receptors than female rats, suggesting that males may respond better to morphine because they are better able to sense it.
Even though other studies have hinted at differences in opioid receptors between males and females, “this work is the first to definitively demonstrate such differences,” says Rebecca Craft, a researcher at Washington State University in Pullman who studies sex differences in pain sensation.
The new study also shows that the female hormonal cycle has a major role in pain relief. Female rats with high estrogen levels had the fewest number of opioid receptors and were the most impervious to morphine. As estrogen levels naturally fell, the numbers of opioid receptors in females approached male levels.
The potential link between female hormones and pain may have been what kept other researchers from using female subjects. Because hormone levels are known to affect many biological processes, including pain, female rats must be at the same hormonal profile to get meaningful results from experiments. Deciphering the precise hormonal stage of a rat relies on time-consuming experiments, and many researchers may wish to avoid the hormone complication altogether by using males, says Murphy.
In the new study, rats received a dose of morphine, and researchers measured how long it took the rats to remove one of their paws from a hot glass plate. The team reasoned that the morphine was not working if the rat removed its paw quickly; if the rat wasn’t feeling pain, it would keep its paw on the hot plate longer. Researchers found that female rats with high estrogen levels yanked their paws away from the heat, even after a morphine shot, suggesting that the morphine did very little to alleviate pain. Males, and also females with low estrogen levels, responded to the painful stimulus more slowly after being injected with morphine once.
Sex differences in human pain response are less clear, although recent brain-scan evidence suggests that men have a stronger response than women to the same amount of morphine. Craft says that while experiments on sex differences in rats are likely important for humans, more research is needed in humans to confirm if such a gender gap exists among them as well.
Age and ethnicity have also been suggested as factors that affect the potency of medicine. Murphy points to the need for pain medication studies that include a wide range of subjects, not just the young males who are typically chosen.
“These studies are going to help enlighten physicians and scientists that males and females are different. You have to have sex-specific medicine,” says Murphy.