MOGILab was the first to demonstrate a qualitative sex difference in pain mechanisms, and has continued to find new examples of sex differences in pain, most quite by accident, simply by always using both sexes in experiments. By demonstrating such sex differences, we have encouraged the field to stop avoiding the use of female subjects (who do not display more variable data than do males).
Quantitative Sex Differences
Although sex differences in pain depend on the genetic background of the subject (see below) and the modality and intensity of the noxious stimulus, MOGILab has re-analyzed the available human evidence to show beyond any doubt that (in contrast to most people’s intuitions on the subject) women are more sensitive to pain than men. It doesn’t matter what type of pain is considered, nor how that pain is measured. Women are also more likely than men to endorse having chronic pain symptoms, and as a result represent the clear majority of chronic pain patients. In preclinical studies, although quantitative sex differences are often observed, often they aren’t, and we have shown that sex accounts for far more variability as a factor interacting with other factors (e.g., strain, environment) than it does by itself.
Genotype (i.e., genetic background) and sex interact, such that sex differences are only observed in some genotypes and some genotype differences are only observed in one sex. Notable interactions demonstrated by MOGILab include the following:
- In an experiment investigating analgesia produced by intracerebroventricular administration of morphine, we found that out of 11 strains examined, 3 strains displayed significant male>female analgesia (AKR, C57BL/6, SWR), and 1 strain displayed significant female>male analgesia (CBA), with the rest displaying no sex difference.
- In an experiment investigating mechanical pain hypersensitivity (allodynia) after nerve injury, female rats of three strains displayed significant differences, but male rats of the same strains did not.
- A study of the thermal pain sensitivity of six outbred mice and rat strains revealed one strain in which males were more sensitive than females, two in which females were more sensitive than males, and three showing no sex differences. In this same study we found that estrus cycle can interact with genotype as well, with one mouse strain but not another showing differential morphine analgesic sensitivity in proestrus.
- A human association study of the OPRM1 gene showed that pressure pain thresholds were affected by genotype in men but not women.
- We demonstrated a three-way gene-sex-environment interaction in mice and humans, in which polymorphisms of the AVPR1A gene affect capsaicin pain levels, but only in men reporting stress at the time of testing.
Qualitative Sex Differences
MOGILab is continually demonstrating that in addition to the existence of quantitative sex differences, in which male and female mice have different amounts of pain or analgesia, males and females process pain in a remarkably independent fashion. The following qualitative sex differences have been demonstrated (in chronological order):
- antagonism of stress-induced analgesia by NMDA receptor blockade in male mice; no such blockade in females (testosterone-dependent)
- antagonism of stress-induced analgesia by opioid receptor blockade in male mice (DBA/2 strain); no such blockade in females
- involvement of Oprd1 gene in thermal pain in male but not female mice
- involvement of a gene on chromosome 8 (later found to be MC1R) in stress-induced analgesia and kappa-opioid analgesia in female but not male mice and humans (progesterone-dependent)
- bidirectional (dose-dependent) modulation of morphine analgesia by non-competitive NMDA receptor antagonists in male mice; no such modulation in females
- involvement of the OPRM1 gene in pressure pain sensitivity in men but not women
- much stronger genetic linkage of the Calca (calcitonin gene-related peptide) gene with thermal pain sensitivity in male versus female mice
- potentiation of inflammatory pain sensitivity by the ASIC blocker, amiloride, in female but not male mice
- mediation of opioid-induced hyperalgesia by NMDA receptors in male mice, but melanocortin-1 receptors in female mice
- social approach to cagemates in pain by female but not male mice
- same-sex conspecific proximity-induced hyperalgesia in male but not female mice
- involvement of the vasopressin-1A receptor in stress-induced analgesia in male but not female mice and humans
- involvement of toll-like receptor 4 (TLR4) in inflammatory and neuropathic pain in male but not female mice
- reduction of sexual libido by pain in female but not male mice
- chronic pain is mediated by spinal cord microglia only in male mice (and male rats); instead by T cells in female mice (also see here)
- male mice in pain are less likely to co-occupy a tube with other males; no difference in female mice
- previously dominant male mice in neuropathic pain lose their dominance status; no change of dominance status in females
- classically conditioned pain hypersensitivity in male mice and humans; not observed in females of both species
- involvement of the MRAS gene in temporomandibular disorder risk in men but not women
- miR-19b levels in blood predict the development of widespread pain and stress after trauma in men but not women
- male mice with neuropathic pain from spared nerve injury (SNI) display unaltered mechanical allodynia out to 12 months post-injury; female mice recover completely
- identification by single-cell RNA sequencing of microglia of a cluster of genes whose expression is induced by spared nerve injury (SNI) in male but not female mice
- classically conditioned analgesia in female mice given repeated exposures to pain; male mice display either no effect or conditioned hyperalgesia
- starting no less than 4 months after a spared nerve injury causing neuropathic pain, male but not female mice display telomere length reduction in microglia and p53-mediated cellular senescence, such that pain is maintained in male mice only at long time points after injury
In a paper currently submitted, we look at even longer time points after injury (almost 3 years in a few mice), and find a sex-specific impact of chronic pain on mortality in the mouse. Stay tuned!