Summary: The microglia in women’s brains are more active in regions involved in pain processing, a new study reports.
Source: Georgia State University.
A female brain’s resident immune cells are more active in regions involved in pain processing relative to males, according to a recent study by Georgia State University researchers.
The study, published in the Journal of Neuroscience, found that when microglia, the brain’s resident immune cells, were blocked, female response to opioid pain medication improved and matched the levels of pain relief normally seen in males.
Women suffer from a higher incidence of chronic and inflammatory pain conditions such as fibromyalgia and osteoarthritis. While morphine continues to be one of the primary drugs used for the treatment of severe or chronic pain, it is often less effective in females.
“Indeed, both clinical and preclinical studies report that females require almost twice as much morphine as males to produce comparable pain relief,” said Hillary Doyle, graduate student in the Murphy Laboratory in the Neuroscience Institute of Georgia State. “Our research team examined a potential explanation for this phenomenon, the sex differences in brain microglia.”
In healthy individuals, microglia survey the brain, looking for signs of infection or pathogens. In the absence of pain, morphine interferes with normal body function and is viewed as a pathogen, activating the brain’s innate immune cells and causing the release of inflammatory chemicals such as cytokines.
To test how this sex difference affects morphine analgesia, Doyle gave male and female rats a drug that inhibits microglia activation.
“The results of the study have important implications for the treatment of pain, and suggests that microglia may be an important drug target to improve opioid pain relief in women,” said Dr. Anne Murphy, co-author on the study and associate professor in the Neuroscience Institute at Georgia State.
The research team’s finding that microglia are more active in brain regions involved in pain processing may contribute to why the incidence rates for various chronic pain syndromes are significantly higher in females than males.
Funding: Funding support for the study was provided by National Institutes of Health.
Source: Brian Mullen – Georgia State University
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “Sex Differences in Microglia Activity within the Periaqueductal Gray of the Rat: A Potential Mechanism Driving the Dimorphic Effects of Morphine” by H.H. Doyle, L.N. Eidson, D.M. Sinkiewicz and A.Z. Murphy in Journal of Neuroscience. Published online February 20 2017 doi:10.1523/JNEUROSCI.2906-16.2017
Sex Differences in Microglia Activity within the Periaqueductal Gray of the Rat: A Potential Mechanism Driving the Dimorphic Effects of Morphine
Although morphine remains the primary drug prescribed for alleviation of severe or persistent pain, both preclinical and clinical studies have shown that females require 2-3 times more morphine than males to produce comparable levels of analgesia. In addition to binding to the neuronal μ opioid receptor (MOR), morphine binds to the innate immune receptor toll-like receptor 4 (TLR4) localized primarily on microglia. Morphine action at TLR4 initiates a neuroinflammatory response that directly opposes the analgesic effects of morphine. Here we test the hypothesis that the attenuated response to morphine observed in females is the result of increased microglia activation in the periaqueductal gray (PAG), a central locus mediating the antinociceptive effects of morphine. We report that while no overall sex differences in the density of microglia were noted within the PAG of male or female rats, microglia exhibited a more “activated” phenotype in females at baseline, with the degree of activation a significant predictor of morphine ED50 values. Priming microglia with LPS induced greater microglia activation in the PAG of females compared with males that was accompanied by increased transcription levels of IL-1ß and a significant rightward shift in the morphine dose response curve. Blockade of morphine binding to PAG TLR4 with (+)-naloxone significantly potentiated morphine antinociception in females such that no sex differences in ED50 were observed. These results demonstrate that PAG microglia are sexually dimorphic in both basal and LPS-induced activation, and contribute to the sexually dimorphic effects of morphine in the rat.
We demonstrate that PAG microglia contribute to the sexually dimorphic effects of morphine. Specifically, we report that increased activation of microglia in the PAG contributes to the attenuated response to morphine observed in females. Our data further implicate the innate immune receptor TLR4 as an underlying mechanism mediating these effects, and establish that TLR4 inhibition in the PAG of females reverses the sex differences in morphine responsiveness. These data suggest novel methods to improve current opioid-based pain management via inhibition of glial TLR4, and illustrate the necessity for sex-specific research and individualized treatment strategies for the management of pain in men and women.
“Sex Differences in Microglia Activity within the Periaqueductal Gray of the Rat: A Potential Mechanism Driving the Dimorphic Effects of Morphine” by H.H. Doyle, L.N. Eidson, D.M. Sinkiewicz and A.Z. Murphy in Journal of Neuroscience. Published online February 20 2017 doi:10.1523/JNEUROSCI.2906-16.2017