TY - JOUR
T1 - Sex differences in the expression of the endocannabinoid system within V1M cortex and PAG of Sprague Dawley rats
AU - Levine, Aidan
AU - Liktor-Busa, Erika
AU - Lipinski, Austin A.
AU - Couture, Sarah
AU - Balasubramanian, Shreya
AU - Aicher, Sue A.
AU - Langlais, Paul R.
AU - Vanderah, Todd W.
AU - Largent-Milnes, Tally M.
N1 - Funding Information:
The authors would like to acknowledge the assistance of Douglas Cromey, MS, manager for optical microscopes in the Imaging Cores-Life Sciences North. The Zeiss Elyra S.1 Microscope is part of the Imaging Cores-Life Sciences North, which is overseen by the University of Arizona Research Labs (purchase supported by NIH S10 OD019948). University of Arizona Cancer Center’s Analytical Chemistry Shared Resources is acknowledged for the assistance of LC–MS service. The authors acknowledge the assistance of Dean Billheimer, Ph.D., director of the UA Statistical Consulting lab, for statistical analysis and confirming appropriateness of statistical tests used for the data.
Funding Information:
This work was supported by grants from the National Institute of Neurological Disorders and Stroke (R01NS099292, TML) of the National Institutes of Health, Arizona Biomedical Research Commission (ABRC45952, TML), with monies from the Department of Pharmacology at the University of Arizona, the M.D.-Ph.D. Program at the University of Arizona, and the University of Arizona Comprehensive Pain and Addiction Center. Research reported in this publication was also supported by the National Cancer Institute of the National Institutes of Health under Award Number P30 CA023074. Authors are solely responsible for the content which does not necessarily represent the official views of the National Institutes of Health, the State of Arizona, or the University of Arizona.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - Background: Several 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. Methods: Brain 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. Results: Mass 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. Conclusions: Our 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.
AB - Background: Several 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. Methods: Brain 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. Results: Mass 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. Conclusions: Our 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.
KW - 2-Arachidonoylglycerol
KW - Anandamide
KW - Endocannabinoids
KW - Migraine
KW - Pain
KW - Periaqueductal grey
KW - Proteomics
KW - Sex differences
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U2 - 10.1186/s13293-021-00402-2
DO - 10.1186/s13293-021-00402-2
M3 - Article
C2 - 34749819
AN - SCOPUS:85118721347
SN - 2042-6410
VL - 12
JO - Biology of Sex Differences
JF - Biology of Sex Differences
IS - 1
M1 - 60
ER -