ArticlePhysiology & behavior2018
Sex-dependent influences of morphine and its metabolites on pain sensitivity in the rat.
Article in Physiology & behavior, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
28 citing papers in PubMed, 1 synthesis or guideline pooled it, 51 citations in OpenAlex.
- Pooled it
- Reversal of morphine-induced respiratory depression with the µAmerican journal of physiology. Lung cellular and molecular physiology · 2025Article
- Interactive effects of morphine and the HIV integrase inhibitor, cabotegravir, in male and female mice.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2025Article
- Examining the effects of the HIV-1 protein Tat and morphine on antiretroviral accumulation and distribution within the brain.Clinical and translational science · 2024Article
- Fentanyl dysregulates neuroinflammation and disrupts blood-brain barrier integrity in HIV-1 Tat transgenic mice.Journal of neurovirology · 2024Article
- Pain mechanisms in the transgender individual: a review.Frontiers in pain research (Lausanne, Switzerland) · 2024Review
- Sex differences in opioid response: a role for the gut microbiome?Frontiers in pharmacology · 2024Review
- Morphine Withdrawal-Induced Hyperalgesia in Models of Acute and Extended Withdrawal Is Attenuated byInternational journal of molecular sciences · 2023Article
- Heroin- and Fentanyl-Induced Respiratory Depression in a Rat Plethysmography Model: Potency, Tolerance, and Sex Differences.The Journal of pharmacology and experimental therapeutics · 2023Article
- Effects of prenatal opioid exposure on synaptic adaptations and behaviors across development.Neuropharmacology · 2023Review
- Sex differences in chronic pain-induced mental disorders: Mechanisms of cerebral circuitry.Frontiers in molecular neuroscience · 2023Review
- Interleukin-1 receptor-associated kinase 4 (IRAK4) in the nucleus accumbens regulates opioid-seeking behavior in male rats.Brain, behavior, and immunity · 2022Article
- Morphine-3-Glucuronide, Physiology and Behavior.Frontiers in molecular neuroscience · 2022Review
- Acute morphine blocks spinal respiratory motor plasticity via long-latency mechanisms that require toll-like receptor 4 signalling.The Journal of physiology · 2021Article
- Interactive Mechanisms of Supraspinal Sites of Opioid Analgesic Action: A Festschrift to Dr. Gavril W. Pasternak.Cellular and molecular neurobiology · 2021Review
- Hippocampal TNF-α Signaling Mediates Heroin Withdrawal-Enhanced Fear Learning and Withdrawal-Induced Weight Loss.Molecular neurobiology · 2021Article
- κ-Opioid receptor antagonism reverses heroin withdrawal-induced hyperalgesia in male and female rats.Neurobiology of stress · 2021Article
- Sex- and Gender-Based Pharmacological Response to Drugs.Pharmacological reviews · 2021Article
- Sexually dimorphic neuroimmune response to chronic opioid treatment and withdrawal.Neuropharmacology · 2021Article
- Systems and Circuits Linking Chronic Pain and Circadian Rhythms.Frontiers in neuroscience · 2021Review
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Preclinical studies report that the effective dose for morphine is approximately 2-fold higher in females than males. Following systemic administration, morphine is metabolized via Phase II glucuronidation in the liver and brain into two active metabolites: morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), each possessing distinct pharmacological profiles. M6G binds to μ opioid receptors and acts as a potent analgesic. In contrast, M3G binds to toll-like receptor 4 (TLR4), initiating a neuroinflammatory response that directly opposes the analgesic effects of morphine and M6G. M3G serum concentrations are 2-fold higher in females than males, however, sex-specific effects of morphine metabolites on analgesia and glial activation in vivo remain unknown. The present studies test the hypothesis that increased M3G, and subsequent TLR4-mediated activation of glia, is a primary mechanism driving the attenuated response to morphine in females. We demonstrate that intra-PAG M6G results in a greater analgesic response in females than morphine alone. M6G analgesia was reversed with co-administration of (-)-naloxone, but not (+)-naloxone, suggesting that this effect is μ opioid receptor mediated. In contrast, intra-PAG administration of M3G significantly attenuated the analgesic effects of systemic morphine in males only, increasing the 50% effective dose of morphine two-fold (5.0 vs 10.3mg/kg) and eliminating the previously observed sex difference. An increase in IL-1β, IL-6 and TNF was observed in females following intra-PAG morphine or M6G. In males, only IL-1β levels increased following morphine. Changes in cytokine levels following M3G were limited to TNF in females. Together, these data implicate sex differences in morphine metabolism, specifically M3G, as a contributing factor in the attenuated response to morphine observed in females.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.