Painkillers work differently in females than in males
Morphine, the most powerful painkiller we have, does not work the same way in everyone. New research shows that sex and genetics together determine how strong and how lasting its effects are. The implications for chronic pain treatment are significant.
Opioids like morphine act through specific receptors in the brain known as mu-opioid receptors. These bind morphine and transmit a pain-dampening signal. But how long and how intensely that signal lasts varies considerably between individuals, and between males and females.
Two genes, two time windows
The study, published in eLife, tracked the behaviour of nearly 700 mice following a single morphine injection. Researchers measured more than 100 different behavioural responses over three hours, allowing them to map precisely when each gene was steering morphine’s effects.
During the first 75 minutes, the gene Oprm1 (which encodes the mu-opioid receptor) was dominant. After that, a second gene, Fgf12, took over. This gene was particularly active in female mice. The two genes were also found to interact temporarily in what researchers call an epistatic interaction, something not previously demonstrated in mammals for drug response.
Implications for pain management and ageing
Chronic pain is one of the most underappreciated health problems in older adults. As people age, sensitivity to painkillers shifts and the risk of side effects increases. Understanding the genetic basis of how opioids work could help tailor dosing and drug choice more precisely to the individual patient.
The finding that Fgf12 plays a larger role in female mice aligns with the well-established observation that women respond differently to opioids than men. Translating mouse findings to humans requires caution. The researchers found supporting evidence in human genetic data (GWAS analyses), which suggests similar networks may be active in people as well.
The discovery that a temporary cooperation between two genes modulates morphine’s effects opens new avenues for developing pain medication better matched to sex and genetic profile. That matters for everyone, but especially for older adults where therapeutic margins are narrower.
Search terms to explore further: mu-opioid receptor genetic variation, epistatic interaction drug response, sex differences opioid pharmacology