Cited by 166Pain Mechanisms and TreatmentsNeuroinflammation and Neurodegeneration MechanismsNeuropeptides and Animal Physiology

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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

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Doyle, Hillary H., Eidson, Lori N., Sinkiewicz, David M., Murphy, Anne Z.·2017·The Journal of Neuroscience

DOI 10.1523/jneurosci.2906-16.2017PMC PMC5373114

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Abstract

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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Authors: Doyle, H. H., Eidson, L. N., Sinkiewicz, D. M., & Murphy, A. Z.
Affiliations: Georgia State University (US)
ORCID: Doyle, Hillary H.
Murphy, Anne Z.
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
DOI: 10.1523/jneurosci.2906-16.2017
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: cc-by-nc-sa
creativecommons.org/licenses/by-nc-sa/4.0/ (vor, 214 d)
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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Sex Differences in Microglia Activity within the Periaqueductal Gray of the Rat: A Potential Mechanism Driving the Dimorphic Effects of Morphine

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