The missing piece in pain research: understanding sex specific pain pathways

Three scientists from the University of California have published a review in Science called Sex specific mechanisms of chronic pain. This blog is a summary of their article which highlights gaps in our knowledge and a need for scientists to further investigate sex differences in pain processing. Venkataraman, Midavaine and Ingraham lay out what is currently known and show that it boils down to different neuroimmune processes in men and women. When these processes can be targeted then chronic pain conditions will be reduced for everyone.

Yes, hormones play a role

This image shows common pain disorders suffered by women. Our three scientists introduce us to the idea that hormones play a role in women’s pain. There is well documented evidence for menstrual cycle related changes in sensitivity in IBS, interstitial cystitis/ bladder pain syndrome, migraine and endometriosis. Pelvic pain and migraine increases around menstruation and symptoms usually improve after menopause. The current treatment approach utilises hormone based therapies to counteract oestrogen excess and progesterone resistance. Targeting hormones is an incomplete solution however, because this approach doesn’t include the complex mix of non-hormonal, neurological, and structural factors that also contribute to pain. For example:

There are CGRP levels to consider too

Female mice have been found to have a greater abundance of CGRP expressing neurons which points to the reason why more women suffer from migraines than men. On top of this women with endometriosis and migraine show significantly higher serum CGRP levels than control group subjects. CGRP stands for calcitonin gene-related peptide and it is normally a helpful protein. It helps control blood pressure by expanding blood vessels. Excess CGRP activates pain signalling nerves and makes pain last longer. CGRP inhibitors have been developed to prevent migraines (as shown in the image above) and women have shown to be more responsive to this treatment than men. It is only in the past year that scientists have suggested that CGRP inhibitors could help reduce endometriosis symptoms too.

Our gut health plays a role

Women’s guts might be more responsive. This is definitely the case for mice. Female mice have higher baseline activity in colon innervating neurons than males, they also have lower serotonergic cell activation and availability in the gut too. Serotonin helps to calm our nervous system and inhibits pain signalling. Mouse gut microbial dysbiosis after injury also follows distinctly gendered patterns. There is also evidence that transplanting gut microbiota from women with fibromyalgia into germ free mice induces pain and immune changes. This all shows that our gut environment plays a role in mediating pain too.

This image shows that endocrine signals from testosterone, oestrogen and stress hormones interact with our microbes and gut organisms to effect the lining of the colon. Specialised cells in the colon then engage with serotonin receptors and immune mediators (if inflammation is present) and send information towards the spinal cord. These sensory signals are interpreted by pain sensing neurons which propagate messages to the spinal cord and brain - if the signal is strong enough.

The female specific sensory pathway.

For women oestrogen is part of the chemical cascade that up-regulates gut responsiveness to fermentable foods. This results in increased serotonin signalling and pain messaging. Oestrogen also sensitises sensory neurons in the gut, making them fire more easily.

We have different neuro-immune pathways

These images shows the sex dependent neuro-immune mechanisms at play (in mice). They show that after nerve injury, injured neurons release a chemical (colony stimulating factor) to trigger neuro-immune pathways. In females ovarian hormones generate regulatory cells which trigger the production of natural pain relieving chemicals. In males testosterone increases white blood cell production which in turn creates chemicals to dampen and control inflammation thus accelerating pain resolution.

This is where our scientists would like researchers to further investigate. They propose that a new approach to pain could be through finding ways to stimulate a person’s own immune mediated analgesic pathway. Women are waiting for concrete answers to eliminate the “all in your head” approach to their illnesses. It is possible that these underlying mechanisms might be the direction that we should be exploring.

I don’t know if the condescending medieval owls agree but this was all pretty dry so here’s a meme for you:

And that is my oversimplified summary of Sex specific mechanisms of chronic pain.

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