Qualitative sex differences in pain processing: emerging evidence of a biased literature

Abstract

Although most patients with chronic pain are women, the preclinical literature regarding pain processing and the pathophysiology of chronic pain has historically been derived overwhelmingly from the study of male rodents. This Review describes how the recent adoption by a number of funding agencies of policies mandating the incorporation of sex as a biological variable into preclinical research has correlated with an increase in the number of studies investigating sex differences in pain and analgesia. Trends in the field are analysed, with a focus on newly published findings of qualitative sex differences: that is, those findings that are suggestive of differential processing mechanisms in each sex. It is becoming increasingly clear that robust differences exist in the genetic, molecular, cellular and systems-level mechanisms of acute and chronic pain processing in male and female rodents and humans.

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Fig. 1: Analysis of quantitative and qualitative sex differences in the pain literature.

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Acknowledgements

The author is supported by funding from the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada and the Louise and Alan Edwards Foundation.

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related links

Canadian Institute of Health Research - How CIHR is supporting the integration of SGBA: https://cihr-irsc.gc.ca/e/50837.html

NIH Policy on Sex as a Biological Variable: https://orwh.od.nih.gov/sex-gender/nih-policy-sex-biological-variable

Supplementary information

Glossary

Quantitative trait locus

(QTL). The approximate genomic location of a gene variant responsible for a difference between strains, used to identify the gene responsible.

Candidate gene association study

A study of the potential role of a preidentified gene in the mediation of variability in a trait.

Pleiotropy

A situation in which a single gene influences two or more seemingly unrelated traits.

Genome-wide association studies

Studies looking for genetic association between thousands of known DNA variants and a trait of interest.

RNA sequencing

A technique that examines the quantity and sequences of RNA in a sample using next-generation sequencing.

Priming

A short-lasting hypersensitivity state that produces a long-lasting one on the introduction of a second noxious stimulus.

Microgliosis

A reactive change in the structure and function of microglia in response to damage to the CNS.

Schwann cell

A glial cell type in the peripheral nervous system that produce the myelin sheath around axons.

Organizational effects

Permanent effects of hormones on structure and function that occur during development.

Activational effects

Temporary effects of hormones on structure and function that depend on the presence or absence of the hormone.

X inactivation

The process by which one of the two copies of the X chromosome is inactivated in female mammals.

Four-core genotypes model

Strains of mice genetically engineered such that sex chromosome complement (XX vs XY) is unrelated to the animal’s gonadal sex.

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Mogil, J.S. Qualitative sex differences in pain processing: emerging evidence of a biased literature. Nat Rev Neurosci 21, 353–365 (2020). https://doi.org/10.1038/s41583-020-0310-6

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