Evidence map›Paper›PMID 34749819›Full record

ArticleBiology of sex differences2021

Sex differences in the expression of the endocannabinoid system within V1M cortex and PAG of Sprague Dawley rats.

Aidan Levine, Erika Liktor-Busa, Austin A Lipinski, Sarah Couture, Shreya Balasubramanian, Sue A Aicher, Paul R Langlais, Todd W Vanderah, Tally M Largent-Milnes

Open access · goldAbstract read
In one paragraph

Article in Biology of sex differences, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.

0numbers the graph read from it
0cells of the map it votes in
30citing papers in PubMed
5.3field-weighted citation impact, top 4% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

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.

2 · The registry

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.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

30 citing papers in PubMed, 46 citations in OpenAlex.

  1. Article
  2. Article
  3. Review
  4. Cannabinoids rescue migraine symptoms caused by central CGRP administration in mice.Cephalalgia : an international journal of headache · 2025
    Article
  5. Article
  6. Article
  7. Dietary Manganese Modulates Microbiota and Intestinal N-Acylethanolamines in a Sex-Specific Manner in Mice With Diet-Induced Obesity.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025
    Article
  8. Article
  9. Migraine in men.The journal of headache and pain · 2025
    Review
  10. Review
  11. Article
  12. Review
  13. Article
  14. Pathology of pain and its implications for therapeutic interventions.Signal transduction and targeted therapy · 2024
    Review
  15. Article
  16. Article
  17. Article
  18. Article
  19. Article
  20. Cannabinoid Tolerance in S426A/S430A xThe Journal of pharmacology and experimental therapeutics · 2023
    Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

9 authors at 2 institutions in 1 country.

Aidan Levine *Department of Pharmacology, University of Arizona, 1501 N. Campbell Ave., Life Sciences North Rm 621, Tucson, AZ, 85724, USA.
Erika Liktor-Busa *Department of Pharmacology, University of Arizona, 1501 N. Campbell Ave., Life Sciences North Rm 621, Tucson, AZ, 85724, USA.
Austin A LipinskiEndocrinology Division, Department of Medicine, University of Arizona, Tucson, AZ, 85724, USA.
Sarah CoutureDepartment of Pharmacology, University of Arizona, 1501 N. Campbell Ave., Life Sciences North Rm 621, Tucson, AZ, 85724, USA.
Shreya BalasubramanianDepartment of Pharmacology, University of Arizona, 1501 N. Campbell Ave., Life Sciences North Rm 621, Tucson, AZ, 85724, USA.
Sue A AicherDepartment of Chemical Physiology & Biochemistry, Oregon Health & Science University, Portland, OR, 97239, USA.
Paul R LanglaisEndocrinology Division, Department of Medicine, University of Arizona, Tucson, AZ, 85724, USA.
Todd W VanderahDepartment of Pharmacology, University of Arizona, 1501 N. Campbell Ave., Life Sciences North Rm 621, Tucson, AZ, 85724, USA.
Tally M Largent-MilnesDepartment of Pharmacology, University of Arizona, 1501 N. Campbell Ave., Life Sciences North Rm 621, Tucson, AZ, 85724, USA. tlargent@email.arizona.edu.ORCID 0000-0001-7599-102X
University of Arizona · USOregon Health & Science University · US

Funding

VITAMIN AP30CA023074 · NCI · UNIVERSITY OF ARIZONA · PI Teri L Bankhead · 1985 to 2026
$110.2M
Blood Brain Barrier and Migraine: Effect on Therapy (Diversity Supplement)R01NS099292 · NINDS · UNIVERSITY OF ARIZONA · PI MILNES, TALLY MARIE · 2017 to 2021
$1.7M
Structured Illumination Fluorescence MicroscopeS10OD019948 · OD · UNIVERSITY OF ARIZONA · PI ELLIOTT, DAVID A · 2015 to 2015
$517k
Primary Afferent Transmission in the Trigeminal Dorsal HornF32DE022499 · NIDCR · OREGON HEALTH & SCIENCE UNIVERSITY · PI MILNES, TALLY MARIE · 2011 to 2014
$127k
NCI NIH HHS P30 CA023074NIDCR NIH HHS F32 DE022499NIH HHS S10 OD019948NINDS NIH HHS R01 NS099292NINDS NIH HHS R01NS099292
6 · The paper itself

Abstract

backgroundSeveral chronic pain disorders, such as migraine and fibromyalgia, have an increased prevalence in the female population. The underlying mechanisms of this sex-biased prevalence have yet to be thoroughly documented, but could be related to endogenous differences in neuromodulators in pain networks, including the endocannabinoid system. The cellular endocannabinoid system comprises the endogenous lipid signals 2-AG (2-arachidonoylglycerol) and AEA (anandamide); the enzymes that synthesize and degrade them; and the cannabinoid receptors. The relative prevalence of different components of the endocannabinoid system in specific brain regions may alter responses to endogenous and exogenous ligands.

methodsBrain tissue from naïve male and estrous staged female Sprague Dawley rats was harvested from V1M cortex, periaqueductal gray, trigeminal nerve, and trigeminal nucleus caudalis. Tissue was analyzed for relative levels of endocannabinoid enzymes, ligands, and receptors via mass spectrometry, unlabeled quantitative proteomic analysis, and immunohistochemistry.

resultsMass spectrometry revealed significant differences in 2-AG and AEA concentrations between males and females, as well as between female estrous cycle stages. Specifically, 2-AG concentration was lower within female PAG as compared to male PAG (*p = 0.0077); female 2-AG concentration within the PAG did not demonstrate estrous stage dependence. Immunohistochemistry followed by proteomics confirmed the prevalence of 2-AG-endocannabinoid system enzymes in the female PAG.

conclusionsOur results suggest that sex differences exist in the endocannabinoid system in two CNS regions relevant to cortical spreading depression (V1M cortex) and descending modulatory networks in pain/anxiety (PAG). These basal differences in endogenous endocannabinoid mechanisms may facilitate the development of chronic pain conditions and may also underlie sex differences in response to therapeutic intervention.

Indexed as

EndocannabinoidsSex CharacteristicsAnimalsFemaleMalePeriaqueductal GrayProteomicsRatsRats, Sprague-DawleyEndocannabinoids2-ArachidonoylglycerolAnandamideEndocannabinoidsMigrainePainPeriaqueductal greyProteomicsSex differences

Identifiers

PMID34749819
PMCPMC8577021
OpenAlexW3171257044

What OpenQuestion holds

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LicenceCC BY
Read underepoch 390

Registered trials

None linked

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.