Female brain’s resident immune cells are more active
Results from a new study may explain why female patients often require higher doses of morphine – one of the primary drugs for the treatment of chronic or severe pain – than male patients to achieve the same level of relief.
It appears that a type of immune cell called microglia is more active in the pain-processing regions of the female brain.
However, even pain conditions that occur in both sexes – from headaches, migraine, and osteoarthritis knee pain, to fibromyalgia and chronic fatigue syndrome – overwhelmingly affect women more than men.
Yet even though it is clear that such differences exist, it is proving rather difficult to discover whether they are due to actual “sex differences” in pain sensitivity.
For their investigation, senior author Anne Murphy – an associate professor who heads a pain research group in the Neuroscience Institute at Georgia State – and colleagues chose to study morphine, the primary drug for relieving severe or chronic pain.
The researchers note how it is often the case that female patients require much more morphine than male patients to achieve similar analgesic effects.
“Indeed, both clinical and preclinical studies report that females require almost twice as much morphine as males to produce comparable pain relief,” says first author Hillary Doyle, a graduate student in Murphy’s research group.
“Our research team examined a potential explanation for this phenomenon, the sex differences in brain microglia,” she adds.
Microglia are immune cells that protect the brain and the rest of the central nervous system against various types of pathogen or potential causes of disease.
Scientists now understand that microglia form a sophisticated and fast scanning system that immediately detects and responds to injury, causing them to becoming highly active.
Previous studies have shown that morphine not only binds to a receptor located on neurons or nerve cells, it also binds to a receptor located primarily on microglia. This receptor is called innate immune receptor toll-like receptor 4, or TLR4.
The researchers note that when morphine binds to TLR4, it triggers “a neuroinflammatory response that directly opposes the analgesic effects of morphine.”
They, therefore, decided to investigate whether this process might differ in male and female brains, and perhaps offer one explanation for the sex differences in the pain-relieving effect of morphine.
From studying rats, they found that males and females had the same density of microglia in the primary pain-processing region of their brains.
However, the microglia in the female brains appeared to be more active – and the degree of activation significantly predicted the amount of morphine needed to achieve a specific analgesic effect.
Moreover, the team was able to show that the immune receptor TLR4 was involved in this process. When they gave the male and female rats a drug that blocked TLR4, the sex differences in morphine responsiveness disappeared.
The authors say that their findings suggest that blocking TLR4 in microglia may offer a way to improve current opioid-based pain management and “illustrate the necessity for sex-specific research and individualised treatment strategies for the management of pain in men and women.”
Prof Anne Murphy said that “The results of the study have important implications for the treatment of pain, and suggest that microglia may be an important drug target to improve opioid pain relief in women.”
