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Sex Differences in Microglia Activity within the Periaqueductal Gray of the Rat: A Potential Mechanism Driving the Dimorphic Effects of Morphine
Open accessAbstract
Although morphine remains the primary drug prescribed for alleviation of severe or persistent pain, both preclinical and clinical studies have shown that females require two to three times more morphine than males to produce comparable levels of analgesia. In addition to binding to the neuronal μ-opioid receptor, 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, whereas 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 half-maximal antinociceptive dose (ED50) values. Priming microglia with LPS induced greater microglia activation in the PAG of females compared with males and was accompanied by increased transcription levels of IL-1β and a significant rightward shift in the morphine dose–response curve. Blockade of morphine binding to PAG TLR4 with (+)-naloxone potentiated morphine antinociception significantly in females such that no sex differences in ED50were 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. SIGNIFICANCE STATEMENTWe demonstrate that periaqueductal gray (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 toll-like receptor 4 (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.
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“with female cells exhibiting higher pro-inflammatory responses compared to age-matched male cells.67,68”
From Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer’s disease (2025) · cites this paper as [68]
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“Microglia, which are the resident innate immune cells of the CNS, are highly affected by sex hormones [14, 16–20].”
From Sex chromosomes and sex hormones differently shape microglial properties during normal physiological conditions in the adult mouse hippocampus (2025) · cites this paper as [19]
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Cites
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Considering sex as a biological variable will require a global shift in science culture
Shansky, R. M., & Murphy, A. Z. (2021) · Nature Neuroscience · doi:10.1038/s41593-021-00806-8 · Cited by 442
Self-citationMicroglia morphophysiological diversity and its implications for the CNS
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Spinal cord stimulation in chronic pain: evidence and theory for mechanisms of action
Caylor, J. R., Reddy, R. D., Yin, S., Cui, C. L., Huang, M., Huang, C. W., Rao, R., Baker, D. G., Simmons, A. N., Souza, D., et al. (2019) · Bioelectronic Medicine · doi:10.1186/s42234-019-0023-1 · Cited by 251
Metadata
- Authors
- Doyle, H. H., Eidson, L. N., Sinkiewicz, D. M., & Murphy, A. Z.
- Affiliations
- Georgia State University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2017-02-20
- Volume
- 37
- Issue
- 12
- Pages
- 3202-3214
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC5373114
- OpenAlex
- W2589516850
- Cited by
- 166
- References
- 96
- Citations by year
- 2026: 5 · 2025: 16 · 2024: 12 · 2023: 14 · 2022: 19 · 2021: 37 · 2020: 23 · 2019: 16 · 2018: 17 · 2017: 6
- FWCI
- 12.55
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Drug Abuse (R01DA016272)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- sex differences, microglial activation, periaqueductal gray, morphine, TLR4, neuroinflammation, lipopolysaccharide, IL-1β, naloxone, opioid analgesia, pain management
- MeSH terms
- Animals, Cell Count, Dose-Response Relationship, Drug, Drug Resistance, Female, Male, Morphine, Periaqueductal Gray, Sex Characteristics, Rats, Sprague-Dawley, Microglia, Toll-Like Receptor 4, Rats
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